5-Substituted-2-Arylpyridines

ABSTRACT

Novel 5-substituted-2-arylpyridine compounds are provided. Such compounds can act as selective modulators of CRP receptors. The 5-substituted-2-arylpyridine compounds provided herein are useful in the treatment of a number of CNS and periphereal disorders, particularly stress, anxiety, depression, cardiovascular disorders, and eating disorders. Methods of treatment of such disorders and well as packaged pharmaceutical compositions are also provided. Compounds provided are also useful as probes for the localization of CRF receptors and as standards in assays for CRF receptor binding. Methods of using the compounds in receptor localization studies are given.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/292,703 filed May 22, 2001, the teachings of which areincorporated herein by reference.

BACKGROUND

1. Field of the Invention

The present invention relates to 5-substituted-2-arylpyridine compounds.Such compounds bind with high selectivity and/or high affinity to CRF1receptors (Corticotropin Releasing Factor 1 Receptors). Preferredcompounds block, inhibit, activate, or otherwise modulate the activityof the receptors to which they bind. This invention also relates topharmaceutical compositions comprising such compounds and to the use ofsuch compounds in treatment of psychiatric disorders and neurologicaldiseases, including major depression, anxiety-related disorders,post-traumatic stress disorder, supranuclear palsy and feedingdisorders, as well as treatment of immunological, cardiovascular orheart-related diseases, irritable bowel syndrome, and colonichypersensitivity associated with psychopathological disturbance andstress. Additionally this invention relates to the use such compounds asprobes for the localization of CRF1 receptors in cells and tissues.

2. Background of the Invention

Corticotropin releasing factor (CRF), a 41 amino acid peptide, is theprimary physiological regulator of proopiomelanocortin (POMC) derivedpeptide secretion from the anterior pituitary gland. In addition to itsendocrine role at the pituitary gland, immunohistochemical localizationof CRF has demonstrated that the hormone has a broad extrahypothalamicdistribution in the central nervous system and produces a wide spectrumof autonomic, electrophysiological and behavioral effects consistentwith a neurotransmitter or neuromodulator role in brain. There is alsoevidence that CRF plays a significant role in integrating the responseof the immune system to physiological, psychological, and immunologicalstressors.

CRF acts by binding to and modulating the signal transduction activitiesof specific cell surface receptors, including CRF1 receptors and CRF2receptors. These receptors are found at high concentrations in thecentral nervous system (CNS), particularly in certain regions of thebrain. CRF1 receptors are also found outside the CNS.

Clinical data provide evidence that CRF has a role in psychiatricdisorders and neurological diseases including depression,anxiety-related disorders and feeding disorders. A role for CRF has alsobeen postulated in the etiology and pathophysiology of Alzheimer'sdisease, Parkinson's disease, Huntington's disease, progressivesupranuclear palsy and amyotrophic lateral sclerosis as they relate tothe dysfunction of CRF neurons in the central nervous system.

In affective disorder, or major depression, the concentration of CRF issignificantly increased in the cerebral spinal fluid (CSF) of drug-freeindividuals. Furthermore, the density of CRF receptors is significantlydecreased in the frontal cortex of suicide victims, consistent with ahypersecretion of CRF. In addition, there is a bluntedadrenocorticotropin (ACTH) response to CRF (i.v. administered) observedin depressed patients. Preclinical studies in rats and non-humanprimates provide additional support for the hypothesis thathypersecretion of CRF may be involved in the symptoms seen in humandepression. There is also preliminary evidence that tricyclicantidepressants can alter CRF levels and thus modulate the numbers ofCRF receptors in brain.

The mechanisms and sites of action through which conventionalanxiolytics and antidepressants produce their therapeutic effects remainto be fully elucidated. It has been hypothesized however, that they areinvolved in the suppression of CRF hypersecretion that is observed inthese disorders.

CRF has been implicated in the etiology of anxiety-related disorders.CRF produces anxiogenic effects in animals and interactions betweenbenzodiazepine/non-benzodiazepine anxiolytics and CRF have beendemonstrated in a variety of behavioral anxiety models. Preliminarystudies using the putative CRF receptor antagonist α-helical ovine CRF(9-41) in a variety of behavioral paradigms demonstrate that theantagonist produces “anxiolytic-like” effects that are qualitativelysimilar to the benzodiazepines. Neurochemical, endocrine and receptorbinding studies have all demonstrated interactions between CRF andbenzodiazepine anxiolytics providing further evidence for theinvolvement of CRF in these disorders. Chlordiazepoxide attenuates the“anxiogenic” effects of CRF in both the conflict test and in theacoustic startle test in rats. The benzodiazepine receptor antagonist Ro15-1788, which was without behavioral activity alone in the operantconflict test, reversed the effects of CRF in a dose-dependent manner,while the benzodiazepine inverse agonist FG 7142 enhanced the actions ofCRF.

CRF activity has also been implicated in the pathogenesis of certaincardiovascular or heart-related, digestive, degenerative,dermatological, and immunological, diseases and disorders such ashypertension, tachycardia and congestive heart failure, stroke, acne andosteoporosis, as well as in premature birth, psychosocial dwarfism,stress-induced fever, ulcer, diarrhea, post-operative ileus and colonichypersensitivity, e.g., associated with psychopathological disturbanceand stress.

SUMMARY OF THE INVENTION

The invention provides novel compounds of Formula I (shown below). Theinvention also comprises pharmaceutical compositions comprisingcompounds of Formula I and at least one pharmaceutically acceptablecarrier or excipient. Such 5-substituted-2-arylpyridines bind to cellsurface receptors, preferably G-coupled protein receptors, especiallyCRF receptors and most preferably CRF1 receptors. Preferred compounds ofFormula I exhibit high affinity for CRF1 receptors, i.e., they bind to,activate, inhibit, or otherwise modulate the activity of receptors otherthan CRF receptors with affinity constants of less than 1 micromolar,preferably less than 100 nanomolar, and most preferably less than 10nanomolar. Additionally, preferred compounds of Formula I also exhibithigh selectivity for CRF1 receptors.

The invention further comprises methods of treating patients sufferingfrom certain diseases or disorders by administering to such patients anamount of a compound of Formula I effective to reduce signs or symptomsof the disease or disorder. These diseases and disorders include CNSdisorders, particularly affective disorders, anxiety, stress,depression, and eating disorders and also include certain digestivedisorders, particularly irritable bowel syndrome and Crohn's disease.These diseases or disorders further include cardiovascular orheart-related, digestive, degenerative, dermatological, andimmunological, diseases and disorders such as hypertension, tachycardiaand congestive heart failure, stroke, acne and osteoporosis, as well aspremature birth, psychosocial dwarfism, stress-induced fever, ulcer,diarrhea, post-operative ileus and colonic hypersensitivity. The patientsuffering from such diseases or disorders may be a human or other animal(preferably a mammal), such as a domesticated companion animal (pet) ora livestock animal.

According to yet another aspect, the present invention providespharmaceutical compositions comprising a compound of Formula I orpharmaceutically acceptable salts or solvates thereof together with atleast one pharmaceutically acceptable carrier or excipient, whichcompositions are useful for the treatment of the disorders recitedabove. The invention further provides methods of treating patientssuffering from any of these disorders with an effective amount of acompound or composition of Formula I.

Additionally this invention relates to the use of labeled compounds ofFormula I (particularly radiolabeled compounds of this invention) asprobes for the localization of receptors in cells and tissues and asstandards and reagents for use in determining the receptor-bindingcharacteristics of test compounds.

Thus, in a first aspect, the invention is directed to compounds ofFormula I

and the pharmaceutically acceptable salts thereof.

Ar is phenyl, 1-naphthyl or 2-naphthyl, each of which is mono-, di-, ortri-substituted, or Ar is mono-, di-, or tri-substituted heteroaryl,said heteroaryl having from 1 to 3 rings, 5 to 7 ring members in eachring and from 1 to about 3 heteroatoms in at least one of said rings.

R is oxygen or absent.

R₂ is optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted alkoxy,optionally substituted mono or dialkylamino, optionally substitutedalkylthio, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, optionally substituted mono or dialkylcarboxamide,optionally substituted aryl or optionally substituted heteroaryl, saidheteroaryl having from 1 to 3 rings, 5 to 7 ring members in each ringand from 1 to about 3 heteroatoms in at least one of said rings.

R₁, R₃, and R₄ are independently chosen from hydrogen, halogen, nitro,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted alkoxy, optionallysubstituted mono- or di-alkylamino, optionally substituted cycloalkyl,optionally substituted (cycloalkyl)alkyl, optionally substituted(cycloalkyl)oxy, optionally substituted (cycloalkyl)alkoxy, optionallysubstituted alkylthio, optionally substituted alkylsulfinyl, optionallysubstituted alkylsulfonyl, and optionally substituted mono- ordialkylcarboxamide.

Not all of R₁, R₂, R₃, and R₄ in Formula I are unsubstituted alkyl andnot all of R₁, R₃, and R₄ are hydrogen.

DETAILED DESCRIPTION OF THE INVENTION

Chemical Description and Terminology

Prior to setting forth the invention in detail, it may be helpful toprovide definitions of certain terms to be used herein. Compounds of thepresent invention are generally described using standard nomenclature.Certain compounds are described herein using a general formula thatincludes variables. Unless otherwise specified, each variable withinsuch a formula is defined independently of other variables.

In certain situations, the compounds of Formula I may contain one ormore asymmetric elements such as stereogenic centers, stereogenic axesand the like, e.g. asymmetric carbon atoms, so that the compounds canexist in different stereoisomeric forms. These compounds can be, forexample, racemates or optically active forms. For compounds with two ormore asymmetric elements, these compounds can additionally be mixturesof diastereomers. For compounds having asymmetric centers, it should beunderstood that all of the optical isomers and mixtures thereof areencompassed. In addition, compounds with carbon-carbon double bonds mayoccur in Z- and E-forms, with all isomeric forms of the compounds beingincluded in the present invention. Where a compound exists in varioustautomeric forms, the invention is not limited to any one of thespecific tautomers, but rather includes all tautomeric forms. In thesesituations, the single enantiomers, i.e., optically active forms, can beobtained by asymmetric synthesis, synthesis from optically pureprecursors or by resolution of the racemates. Resolution of theracemates can be accomplished, for example, by conventional methods suchas crystallization in the presence of a resolving agent, orchromatography, using, for example a chiral HPLC column.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample, and without limitation, isotopes of hydrogen include tritiumand deuterium and isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-2 R*, then said group mayoptionally be substituted with up to two R* groups and R* at eachoccurrence is selected independently from the definition of R*. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded, and that the substitution results in a stable compound.When a substituent is oxo (i.e., =0), then 2 hydrogens on the atom arereplaced. When aromatic moieties are substituted by an oxo group, thearomatic ring is replaced by the corresponding partially unsaturatedring. For example a pyridyl group substituted by oxo is adihydropyridone.

As indicated above, various substituents of Formula I and Formula IA(described below) are “optionally substituted”. The phrase “optionallysubstituted” indicates that such groups may either be unsubstituted orsubstituted at one or more of any of the available positions, typically1, 2, 3, or 4 positions, by one or more suitable groups such as thosedisclosed herein.

When substituents such as Ar, R₁, R₂, R₃. and R₄, are furthersubstituted, they may be so substituted at one or more availablepositions, typically 1 to 3 or 4 positions, by one or more suitablegroups such as those disclosed herein. Suitable groups that may bepresent on a “substituted” Ar or other group include e.g., halogen;cyano; hydroxyl; nitro; azido; alkanoyl (such as a C₁-C₆ alkanoyl groupsuch as acyl or the like); carboxamido; alkyl groups (includingcycloalkyl groups, having 1 to about 8 carbon atoms, preferably 1, 2, 3,4, 5, or 6 carbon atoms); alkenyl and alkynyl groups (including groupshaving one or more unsaturated linkages and from 2 to about 8,preferably 2, 3, 4, 5 or 6, carbon atoms); alkoxy groups having one ormore oxygen linkages and from 1 to about 8, preferably 1, 2, 3, 4, 5 or6 carbon atoms; aryloxy such as phenoxy; alkylthio groups includingthose having one or more thioether linkages and from 1 to about 8 carbonatoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms; alkylsulfinyl groupsincluding those having one or more sulfinyl linkages and from 1 to about8 carbon atoms, preferably 1, 2, 3, 4, 5, or 6 carbon atoms;alkylsulfonyl groups including those having one or more sulfonyllinkages and from 1 to about 8 carbon atoms, preferably 1, 2, 3, 4, 5,or 6 carbon atoms; aminoalkyl groups including groups having one or moreN atoms and from 1 to about 8, preferably 1, 2, 3, 4, 5 or 6, carbonatoms; aryl having 6 or more carbons and one or more rings, (e.g.,phenyl, biphenyl, naphthyl, or the like, each ring either substituted orunsubstituted aromatic); arylalkyl having 1 to 3 separate or fused ringsand from 6 to about 18 ring carbon atoms, with benzyl being a preferredarylalkyl group; arylalkoxy having 1 to 3 separate or fused rings andfrom 6 to about 18 ring carbon atoms, with O-benzyl being a preferredarylalkoxy group; or a saturated, unsaturated, or aromatic heterocyclicgroup having 1 to 3 separate or fused rings with 3 to about 8 membersper ring and one or more N, O or S atoms, e.g. coumarinyl, quinolinyl,isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidyl, furanyl,pyrrolyl, thienyl, thiazolyl, triazinyl oxazolyl, isoxazolyl,imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, andpyrrolidinyl. Such heterocyclic groups may be further substituted, e.g.with hydroxy, alkyl, alkoxy, halogen and amino.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds or useful syntheticintermediates. A stable compound or stable structure is meant to imply acompound that is sufficiently robust to survive isolation from areaction mixture, and subsequent formulation into an effectivetherapeutic agent.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, having thespecified number of carbon atoms, Thus, the term C₁-C₆ alkyl as usedherein includes alkyl groups consisting of 1 to 6 carbon atoms. WhenC₀-C₄alkyl is used herein in conjunction with another group, forexample, arylC₀-C₄alkyl, the indicated group, in this case aryl, iseither directly bound by a single covalent bond, or attached by an alkylchain having the specified number carbon atoms, in this case from 1 to 4carbon atoms. Examples of alkyl include, but are not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, ands-pentyl. Preferred alkyl groups are C₁-C₈ and C₁-C₆ alkyl groups.Especially preferred alkyl groups are methyl, ethyl, propyl, butyl, and3-pentyl. “Carbhydryl” is intended to include both branched andstraight-chain hydrocarbon groups, which are saturated or unsaturated,having the specified number of carbon atoms.

“Alkenyl” is intended to include hydrocarbon chains of either a straightor branched configuration comprising one or more unsaturatedcarbon-carbon bonds, which may occur in any stable point along thechain, such as ethenyl and propenyl.

“Alkynyl” is intended to include hydrocarbon chains of either a straightor > branched configuration comprising one or more triple carbon-carbonbonds that may occur in any stable point along the chain, such asethynyl and propynyl.

“Alkoxy” represents an alkyl group as defined above with the indicatednumber of carbon atoms attached through an oxygen bridge. Examples ofalkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy,3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and3-methylpentoxy.

As used herein, the term “mono- or di-alkylamino” includes secondary ortertiary alkyl amino groups, wherein the alkyl groups are as definedabove and have the indicated number of carbon atoms. The point ofattachment of the alkylamino group is on the nitrogen. Examples of mono-and di-alkylamino groups include ethylamino, dimethylamino,methyl-propyl-amino.

As used herein, the term “alkylsulfinyl” includes those groups havingone or more sulfoxide (SO) linkage groups and typically from 1 to about8 carbon atoms, more typically 1 to about 6 carbon atoms.

As used herein, the term “alkylsulfonyl” includes those groups havingone or more sulfonyl (SO₂) linkage groups and typically from 1 to about8 carbon atoms, more typically 1 to about 6 carbon atoms.

As used herein, the term “alkylthio” includes those groups having one ormore thioether linkages and preferably from 1 to about 8 carbon atoms,more typically 1 to about 6 carbon atoms.

As used herein, the term “aryl” indicates aromatic groups containingonly carbon in the aromatic ring. Such aromatic groups may be furthersubstituted with carbon or non-carbon atoms or groups. Typical arylgroups contain 1 to 3 separate, fused, or pendant rings and from 6 toabout 0.18 ring atoms, without heteroatoms as ring members. Specificallypreferred aryl groups include phenyl, naphthyl, including 1-naphthyl and2-naphthyl, and biphenyl. The definition of the term “aryl” is notidentical to that of the variable “Ar”.

As used herein, “carbocyclic group” is intended to mean any stable 3- to7-membered monocyclic group, which may be saturated, partiallyunsaturated, or aromatic. In addition to those exemplified elsewhereherein, examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclohexenyl, and phenyl.

“Cycloalkyl” is intended to include saturated hydrocarbon ring groups,having the specified number of carbon atoms, usually from 3 to about 8ring carbon atoms. Preferred cycloalkyl groups have from 3 to 7 ringcarbon atoms. Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl and bridged or caged saturatedring groups such as norbornane or adamantane and the like.

In the term “(cycloalkyl)alkyl”, cycloalkyl and alkyl are as definedabove, and the point of attachment is on the alkyl group. This termencompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl,and cyclohexylmethyl. Likewise, in the term “(cycloalkyl)alkoxy”,cycloalkyl and alkoxy are as define above, and the point of attachmentin the oxygen of the alkoxy group. The term “cycloalkyloxy” indicates acycloalkyl group, as defined above, attached through an oxygen bridge.

“Cycloalkenyl” is intended to include hydrocarbon ring groups, havingthe specified number of carbon atoms, usually from 3 to about 8 ringcarbon atoms, which have at least one carbon-carbon double bond.Preferred cycloalkyl groups have from 3 to 7 ring carbon atoms. Examplesof cycloalkenyl groups include cyclopentenyl, and cyclohexenyl groups.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen atoms. Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined above attachedthrough an oxygen bridge.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, oriodo.

As used herein, She terms “heteroaryl” is intended to indicate a stable5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclicheterocyclic ring which contains at least 1 aromatic ring that containsfrom 1 to 4 heteroatoms selected from N, O, and S, with remaining ringatoms being carbon. When the total number of S and 0 atoms in theheteroaryl group exceeds I, it is understood that these heteroatoms arenot adjacent to one another. It is preferred that the total number of Sand 0 atoms in the heterocycle is not more than 1, 2, or 3, moretypically 1 or 2. It is particularly preferred that the total number ofS and O atoms in the aromatic heterocycle is not more than 1. Examplesof heteroaryl groups include pyridyl, indolyl, pyrimidinyl, pyridizinyl,pyrazinyl, imidazolyl, oxazolyl, thienyl, thiazolyl, triazolyl,isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, and5,6,7,8-tetrahydroisoquinoline.

The term “heterocycloalkyl” is used to indicate saturated cyclic groupscontaining from 1 to about 3 heteroatoms selected from N, O, and S, withremaining ring atoms being carbon. Heterocycloalkyl groups have from 3to about 8 ring atoms, and more typically have from 5 to 7 ring atoms.Examples of heterocycloalkyl groups include morpholinyl, piperazinyl,and pyrrolidinyl groups.

As used herein, the term “heterocyclic group” is intended to include 3to 7 membered saturated, partially unsaturated, or aromatic monocyclicgroups having at least one atom selected from N, O or S. The remainingring atoms are carbon. The nitrogen and sulfur heteroatoms mayoptionally be oxidized. The heterocyclic ring may be attached to itspendant group at any heteroatom or carbon atom that results in a stablestructure. The heterocyclic rings described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. Anitrogen atom in the heterocycle may optionally be quaternized. It ispreferred that the total number of heteroatoms in the heterocyclicgroups is not more than 4 and that the total number of S and O atoms inthe heterocyclic group is not more than 2, more preferably not more than1.

Preferred heterocyclic groups include, but are not limited to,pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, and imidazolyl.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking non-toxic acid or base salts thereof, and further refers topharmaceutically acceptable solvates of such compounds and such salts.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, dibesylic, sulfanilic, 2-acetoxybenzoic,fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,isethionic, HOOC—(CH₂)n-COOH where n is 0-4, and the like. Thepharmaceutically acceptable salts of the present invention can besynthesized from a parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting free acid forms of these compounds with astoichiometric amount of the appropriate base (such as Na, Ca, Mg, or Khydroxide, carbonate, bicarbonate, or the like), or by reacting freebase forms of these compounds with a stoichiometric amount of theappropriate acid. Such reactions are typically carried out in water orin an organic solvent, or in a mixture of the two. Generally,non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are preferred, where practicable. Lists of additionalsuitable salts may be found, e.g., in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418(1985).

“Prodrugs” are intended to include any compounds that become compoundsof Formula I when administered to a mammalian subject, e.g., uponmetabolic processing of the prodrug. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate and like derivativesof functional groups (such as alcohol or amine groups) in the compoundsof Formula I.

The term “therapeutically effective amount” of a compound of thisinvention means an amount effective, when administered to a human ornon-human patient, to provide a therapeutic benefit such as anamelioration of symptoms, e.g., an amount effective to antagonize theeffects of pathogenic levels of CRF or to treat the symptoms of stressdisorders, affective disorder, anxiety or depression.

CRF1 Receptor Ligands

The present invention is based, in part, on the discovery that smallmolecules having the general Formula I, shown above (as well aspharmaceutically acceptable salts and prodrugs thereof) act asantagonists and/or inverse agonists of CRF1 receptors.

In addition to compounds and pharmaceutically acceptable salts ofFormula I set forth above, the invention provides certain compounds ofFormula I in which R₁, R₃, and R₄ carry the values set forth above forFormula I.

Ar, in this embodiment, is naphthyl, phenyl, pyridyl, pyrimidinyl,pyrazinyl, pyridizinyl, or thiophenyl, each of which is mono-, di-, ortri-substituted.

R₂ is optionally substituted alkyl, optionally substituted alkoxy,optionally substituted mono or dialkylamino, optionally substitutedalkylthio, optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, or optionally substituted mono or dialkylcarboxamide, orR₂ is selected from the group consisting of phenyl, naphthyl, pyridyl,pyrimidinyl, pyrazinyl, pyridizinyl, and thiophenyl, each of which isoptionally mono-, di-, or tri-substituted.

The invention also provides compounds and pharmaceutically acceptablesalts of Formula I in which R₁, R₃, and R₄ carry the values set forthabove for Formula I.

Ar, in this embodiment of the invention, is phenyl or pyridyl, each ofwhich is substituted in at least 1 position ortho to the point ofattachment of Ar in Formula I, and optionally substituted with up to 4additional substituents;

R is absent.

R₂ selected from optionally substituted alkyl, optionally substitutedalkoxy, and optionally substituted mono or di-alkylamino.

The invention also includes compounds and pharmaceutically acceptablesalts of Formula I wherein Ar, R, R₁, R₂, R₁, and R₄ carry the followingdefinitions.

Ar, in this embodiment, is selected from the group consisting of phenyl,naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, and thiophenyl,each of which is substituted with up to 5 R_(A) groups.

R is oxygen or absent.

R₁, R₃, and R₄ are independently selected from hydrogen, halogen,hydroxy, amino, nitro, C₁-C₆carbhydryl₁, C₁-C₆carbhydryl₁-O—, mono- ordi-C₁-C₆carbhydryl₁ amino, C₃-C₇cycloalkyl₂(C₀-C₄-carbhydryl₁),C₃-C₇cycloalkenyl₂(C₀-C₄carbhydryl₁),C₃-C₇cycloalkyl₂(C₀-C₄-carbhydryl₁)—O—,C₃-C₇cycloalkenyl₂(C₀-C₄-carbhydryl₁)—O—, haloC₁-C₆-carbhydryl₁,haloC₁-C₆-carbhydryl₁-O—, and —S(O)_(n)(C₁-C₆-carbhydryl₁), where eachcarbhydryl₁ is independently straight or branched, contains 0 or 1 ormore double or triple bonds, and is unsubstituted or substituted withone or more substituents independently chosen from halogen, hydroxy,oxo, cyano, C₁-C₄alkoxy, amino, and mono- or di-(C₁-C₄alkyl)amino, andwhere each C₁-C₄cycloalkyl and C₃-C₇cycloalkenyl₂ is optionallysubstituted by one or more substituents independently chosen fromhalogen, hydroxy, oxo, cyano, C₁-C₄alkoxy, amino, and mono- ordi-(C₁-C₄)alkylamino.

R₂ is selected from the group consisting of —XR_(C) and Y.

X is independently selected at each occurrence from the group consistingof —CH₂—, —CHR_(D)—, —O—, —C(═O)—, —C(═O)O—, —S(O)O—, —NH—, —NR_(D)—,—C(═O)NH—, —C(═O)NR_(D)—, —S(O)_(n)NH—, —S(O)_(n)NR_(D)—, —OC(═S)S—,—NHC(═O)—, —NR_(D)C(═O)—, —NHS(O)—, and —NR_(D)S(O)_(n)—; n is 0, 1, or2.

Y and Z are independently selected at each occurrence from: 3- to7-membered carbocyclic or heterocyclic groups, which are saturated,partially unsaturated, or aromatic, which may be further substitutedwith one or more substituents independently selected from halogen, oxo,hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, mono- ordi-(C₁-C₄alkyl)amino, and —S(O)_(n)(alkyl), wherein said 3- to7-membered heterocyclic groups contain from 1 to 3 heteroatom(s)independently selected from N, O, and S, with remaining ring membersbeing carbon.

R_(A) is independently selected at each occurrence from halogen, cyano,nitro, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, hydroxy, amino, C₁-C₆alkylsubstituted with 0-2R_(B), C₂-C₆alkenyl substituted with 0-2 R_(B),C₂-C₆alkynyl substituted with 0-2 R_(B), C₃-C₇cycloalkyl substitutedwith 0-2 R_(B), (C₃-C₇cycloalkyl)C₁-C₄alkyl substituted with 0-2 R_(B),C₁-C₆alkoxy substituted with 0-2 R_(B), —NH(C₁-C₆alkyl) substituted with0-2 R_(B), —N(C₁-C₆alkyl)(C₁-C₆alkyl) where each C₁-C₆alkyl isindependently substituted with 0-2 R_(B), —XR_(C), and Y.

R_(B) is independently selected at each occurrence from halogen,hydroxy, cyano, amino, C₁-C₄alkyl, C₁-C₄alkoxy, mono- ordi-(C₁-C₄alkyl)amino, —S(O)_(n)(alkyl), halo(C₁-C₄)alkyl,halo(C₁-C₄)alkoxy, —CO(C₁-C₄alkyl), —CONH(C₁-C₄alkyl),—CON(C₁-C₄alkyl)(C₁-C₄alkyl), —XR_(C), and Y.

R_(C) and R_(D), are die same or different, and are independentlyselected at each occurrence from hydrogen, and straight, branched, andcyclic alkyl groups, and (cycloalkyl)alkyl groups, having 1 to 8 carbonatoms, and containing zero or one or more double or triple bonds, eachof which 1 to 8 carbon atoms may be further substituted with one or moresubstituent(s) independently selected from oxo, hydroxy, halogen, cyano,amino, C₁-C₆alkoxy, mono- or di-(C₁-C₄alkyl)amino, —NHC(═O)(C₁-C₆alkyl),—N(C₁-C₆alkyl)C(═O)(C₁-C₆alkyl), —S(O)_(n)N(C₁-C₆alkyl)(C₁-C₄alkyl), andZ; and n is independently selected at each occurrence from 0, 1, and 2;

Not all of R₁, R₂, R₃, and R₄ are unsubstituted alkyl and not all of R₁,R₃, and R₄ are hydrogen.

Such compounds will be referred to as compounds of Formula IA.

In certain embodiment the invention includes compounds andpharmaceutically acceptable salts of Formula IA in which R is absent andAr is phenyl or pyridyl, each of which is substituted by R_(A) in atleast 1 position ortho to the point of attachment of Ar in Formula I,and optionally substituted with up to 2 additional R_(A) groups.

Preferred compounds of this embodiment include those in which R isabsent, and

R₁, R₃, and R₄ are independently selected from the group consisting ofi) hydrogen, ii)halogen, iii) C₁-C₃alkyl iv) C₁-C₃alkoxy v)(C₃-C₇cycloalkyl)C₀-C₃alkyl, vi) (C₃-C₇cycloalkyl)C₀-C₃alkoxy, vii)mono- or di-(C₁-C₃alkyl)amino, viii) C₁-C₆haloalkyl, and ix)C₁-C₃haloalkoxy wherein each of iii, iv, v, vi, and vii is unsubstitutedor substituted by 1-3 groups independently chosen from hydroxy, amino,cyano, and halogen.

The invention also includes certain compounds and pharmaceuticallyacceptable salts of Formula IA in which R is absent.

Ar, in this embodiment, is phenyl or pyridyl, each of which issubstituted by R_(A) in at least 1 position ortho to the point ofattachment of Ar in Formula I, and optionally substituted with up to 2additional R_(A) groups; and

R_(C) and R_(D), which may be die same or different, are independentlyselected at each occurrence from straight, branched, or cyclic alkylgroups having from 1 to 8 carbon atoms, which alkyl groups may containone or more double or triple bonds.

Preferred compounds of (his class includes those wherein R₁, R₃ and R₄are independently selected from the group consisting of i) hydrogen, ii)halogen, iii) C₁-C₃alkyl, iv) C₁-C₃alkoxy, v)(C₃-C₇cycloalkyl)C₀-C₃alkyl, v) (C₃-C₇cycloalkyl)C₀-C₃alkoxy, vii) mono-or di-(C₁-C₃alkyl)amino, viii)C₁-C₃haloalkyl, and ix) C₁-C₃haloalkoxy,wherein each of iii, iv, v, vi, and vii is unsubstituted or substitutedby 1-3 groups independently chosen from hydroxy, amino, cyano, andhalogen.

The invention is also directed to compounds and pharmaceuticallyacceptable salts of Formula IA in which R is absent.

Ar, in this embodiment of the invention, is phenyl or pyridyl, each ofwhich is substituted in at least one position ortho to the point ofattachment of Ar in Formula I with a substituent selected from halogen,cyano, nitro, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, hydroxy, amino,C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₆alkynyl, C₃-C₇cycloalkyl,(C₃-C₇cycloalkyl)C₁-C₄alkyl, C₁-C₆alkoxy, and mono- ordi-(C₁-C₆alkyl)amino and optionally substituted with up to 2 additionalsubstituents independently selected from halogen, cyano, nitro,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, hydroxy, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₃-C₇alkynyl, C₃-C₇cycloalkyl,(C₃-C₇cycloalkyl)C₁-C₄alkyl, C₁-C₆alkoxy, and mono- ordi-(C₁-C₆alkyl)amino.

R₁, R₃ and R₄ are independently selected from the group consisting of i)hydrogen, ii) halogen, iii) C₁-C₃alkyl, iv) C₁-C₃alkoxy, v)(C₃-C₇cycloalkyl)C₀-C₃alkyl, vi) (C₃-C₇cycloalkyl)C₀-C₃alkoxy, vii)mono- or di-(C₁-C₃alkyl)amino, viii) C₁-C₃haloalkyl, and ix)C₁-C₃haloalkoxy, wherein each of iii, iv, v, vi, and vii isunsubstituted or substituted by 1-3 groups independently chosen fromhydroxy, amino, cyano, and halogen.

Preferred compounds of this class are those wherein R₂ is —XR_(C) and Xis independently selected at each occurrence from the group consistingof —CH—, —CHR_(D)—, —O—, —C(═O)—, —NH—, —NR_(D)—, —C(═O)NH—,—C(═O)NR_(D)—, —NHC(═O)—, —NR_(D)C(═O)—.

It is also preferred that R_(C) and R_(D), are the same or different,and are independently selected at each occurrence from: hydrogen, andstraight, branched, and cyclic alkyl groups, and (cycloalkyl)alkylgroups, having 1 to 8 carbon atoms, and containing zero or one or moredouble or triple bonds, each of which 1 to 8 carbon atoms may be furthersubstituted with one or more substituent(s) independently selected fromoxo, hydroxy, halogen, cyano, amino, C₁-C₆alkoxy, and mono- and di(C₁-C₆alkyl)amino.

More preferably, X is independently selected at each occurrence from thegroup consisting of —CH₂—, —CHR_(D)—, —O—, —NH—, and NR_(D)—, and R_(C)and R_(D), are the same or different, and are independently selected ateach occurrence from: hydrogen, and straight, branched, and cyclic alkylgroups, and (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms, andcontaining zero or one or more double or triple bonds.

A particular aspect of the invention is directed to compounds of FormulaII

or a pharmaceutically acceptable sail thereof.

Ar, R₁, R₃, and R₄ carry the definitions set forth for compounds ofFormula IA, above.

R_(X) and R_(Y) are the same or different and are independently selectedfrom a) hydrogen,

b)-(C═O)C₁-C₈alkyl; and c) straight or branched alkyl groups, cycloalkylgroups, or (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms andcontaining zero or more double or triple bonds, each of which 1 to 8carbon atoms may be further substituted with one or more substituent(s)independently selected from:

i) halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono- ordi-(C₁-C₄alkyl)amino, and

ii) 3- to 7-membered carbocyclic or heterocyclic groups which aresaturated, partially unsaturated, or aromatic, which may be furthersubstituted with one or more substituents independently selected fromhalogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono- ordi-(C₁-C₄alkyl)amino, wherein said 3- to 7-membered heterocyclic groupscontain from 1 to 3 heteroatom(s) independently selected from N, O, andS, with remaining ring members being carbon.

Preferred compounds of Formula II are those wherein R₁, R₃ and R₄ areindependently selected from the group consisting of i) hydrogen,ii)halogen, iii) C₁-C₄alkyl, iv) C₁-C₃alkoxy, v)(C₃-C₇cycloakyl)C₀-C₃alkyl, vi) (C₁-C₇cycloalkyl)C₀-C₃alkoxy, vii) mono-or di-(C₁-C₃alkyl)amino, viii) C₁-C₃haloalkyl, and ix) C₁-C₃haloalkoxy,wherein each of iii, iv, v, vi, and vii is unsubstituted or substitutedby 1-3 groups independently chosen from halogen, hydroxy, oxo, cyano,C₁-C₄alkoxy, amino, and mono- or di-(C₁-C₄alkyl)amino.

An additional embodiment of the invention includes compounds andpharmaceutically acceptable salts of Formula II, wherein R₁, R₃, and R₄carry the definitions set forth for Formula IA.

R_(X) and R_(Y), in this embodiment of the invention, are the same ordifferent and are independently selected from: a) hydrogen,b)-(C═O)C₁-C₃alkyl and c) straight or branched alkyl groups, cycloalkylgroups, or (cycloalkyl)alkyl groups, having 1 to 8-carbon atoms andcontaining zero or more double or triple bonds, each of which 1 to 8carbon atoms may be further substituted with one or more substituent(s)independently selected from: halogen, hydroxy, amino, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, and mono- or di-(C₁-C₄alkyl)amino.

Ar is phenyl or pyridyl, each of which is mono-, di-, or tri-substitutedwith R_(A), (which carries the definition set forth for compounds ofFormula IA) with the proviso that at least one of the positions ortho tothe point of attachment of Ar shown in Formula II is substituted.

X is independently selected at each occurrence from the group consistingof —CH₂—,

-   —CHR_(D)—, —O—, —C(═O)—, —C(═O)O—, —NH—, —NR_(D), —C(═O)NH—,    —C(═O)NR_(D)—, —NHC(═O)—, and —NR_(D)C(═O)—.

Y and Z are independently selected at each occurrence from: 3- to7-membered carbocyclic or heterocyclic groups which are saturated,partially unsaturated, or aromatic, which may be further substitutedwith one or more substituents independently selected from halogen, oxo,hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, mono- ordi-(C₁-C₄alkyl)amino, wherein said 3- to 7-membered heterocyclic groupscontain from 1 to 3 heteroatom(s) independently selected from N, O, andS, with remaining ring members being carbon; and R_(C) and R_(D), arethe same or different, and are independently selected at each occurrencefrom: hydrogen, and straight, branched, and cyclic alkyl groups, and(cycloalkyl)alkyl groups, having 1 to 8 carbon atoms, and containingzero or one or more double or triple bonds, each of which 1 to 8 carbonatoms may be further substituted with one or more substituent(s)independently selected from oxo, hydroxy, halogen, cyano, amino,C₁-C₆alkoxy, mono- or di-(C₁-C₄alkyl)amino, —NHC(═O)(C₁-C₆alkyl),—N(C₁-C₆alkyl)C(═O)(C₁-C₆alkyl), and Z.

Preferred compounds of this class are those wherein R_(X) is a) hydrogenor b) a straight or branched alkyl group, a cycloalkyl groups, or(cycloalkyl)alkyl group, each of which groups having 1 to 8 carbon atomsand containing zero or more double or triple bonds, each of which 1 to 8carbon atoms may be further substituted with one or more substituent(s)independently selected from halogen, hydroxy, amino, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, and mono- or di-(C₁-C₄)alkylamino.

R_(Y), is preferably, a straight or branched alkyl group, a cycloalkylgroups, or (cycloalkyl)alkyl group, each of which groups having 1 to 8carbon atoms and containing zero or more double or triple bonds, each ofwhich 1 to 8 carbon atoms may be further substituted with one or moresubstituent(s) independently selected from halogen, hydroxy, amino,cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono- or di-(C₁-C₄)alkyl amino.

Ar is phenyl or pyridyl, mono-, di-, or tri-substituted withsubstituents independently selected at each occurrence from halogen,cyano, nitro, halo(C₁-C₆)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino,C₁-C₄alky, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl,(C₃-C₇cycloalkyl)C₁-C₄alkyl, C₁-C₆alkoxy, and mono- ordi-(C₁-C₆alkyl)amino.

R₁, R₃ and R₄ are independently selected from the group consisting ofhydrogen, halogen, C₁-C₄alkyl, C₁-C₃alkoxy, (C₃-C₇cycloalkyl)C₀-C₃alkyl,(C₃-C₇cycloalkyl)C₀-C₃alkoxy, mono- or di-(C₁-C₃alkyl)amino,C₀-C₃haloalkyl, and C₁-C₃haloalkoxy.

Particularly preferred compounds of this class are those wherein R_(X)is hydrogen,

-   C₁-C₆-alkyl, a C₃-C₇cycloalkyl, or (C₃-C₇cycloalkyl) C₁-C₄alkyl;    R_(Y) a C₁-C₆alkyl, a C₃-C₇cycloalkyl, or (C₃-C₇cycloalkyl)    C₁-C₄alkyl.

Ar is phenyl or pyridyl, mono-, di-, or tri-substituted withsubstituents independently selected at each occurrence from halogen,halo(C₁-C₂)alkyl, halo(C₁-C₂)alkoxy, hydroxy, amino, C₁-C₃alkyl,C₁-C₂)alkoxy, and mono- or di-(C₁-C₂alkyl)amino.

R₁ and R₄ are independently selected from the group consisting ofhydrogen, halogen, C₁-C₃alkyl, C₁-C₃alkoxy, mono- ordi-(C₁-C₃alkyl)amino, C₁-C₃haloalkyl, and C₁-C₃haloalkoxy; and R₃ ishydrogen, halogen, or methyl.

Other preferred values of R₁ for compounds and salts Formula II includemethyl, methoxy, ethyl and ethoxy.

Preferred R_(X)R_(Y)N— combinations for compounds of Formula II includepropyl-amino, dipropyl-amino, propyl-cyclopropylmethyl-amino,propyl-isopropyl-amino, propyl-(3-methylbutyl)-amino,propyl-benzyl-amino, propyl-(3-pyridylmethyl)-amino, propyl-ethyl-amino,and propyl-butyl-amino groups. R_(X)R_(Y)N— combinations in which R_(X)is hydrogen and R_(Y) is cyclopropylemethyl or a branched alkyl grouphaving 3 to 6 carbon atoms are particularly preferred.

For compounds of Formula II it is also preferred that R₃ is hydrogen orchloro.

Preferred values of R₄ include methyl, ethyl, methoxy, ethoxy, andhalogen. Methyl, ethyl and bromo are particularly preferred.

A further embodiment of the invention includes compounds of Formula III

and the pharmaceutically acceptable salts thereof.

R_(X), R_(Y), R₁, R₃, and R₄ carry the definitions set forth forcompounds of Formula II, above.

A is CH or N.

R₅, R₆ and R₇ are independently i) hydrogen, halogen, cyano,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino, C₁-C₆alkyl,C₁-C₆alkoxy, (C₁-C₄alkoxy) C₁-C₄alkoxy, or mono- or di(C₁-C₄alkyl)amino,or ii) C₁-C₆alkyl or C₁-C₆alkoxy, each of which is further substitutedwith a 3- to 7-membered carbocyclic or heterocyclic groups which issaturated, partially unsaturated, or aromatic, which may be furthersubstituted with one or more substituents independently selected fromhalogen, oxo, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono-or di-(C₁-C₄alkyl)amino.

At least one of R₅ and R₇ is not hydrogen.

An embodiment of the invention is directed to compounds of Formula IIIwherein R_(X) is a) hydrogen or b) a straight or branched alkyl group, acycloalkyl group, or (cycloalkyl)alkyl group, having 1 to 8 carbon atomsand containing zero or more double or triple bonds, each of which 1 to 8carbon atoms may be further substituted with one or more substituent(s)independently selected from halogen, hydroxy, amino, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, and mono- or di-(C₁-C₄alkylamino.

R_(Y) is a straight or branched alkyl group, a cycloalkyl group, or(cycloalkyl)alkyl group, each having 1 to 8 carbon atoms and containingzero or more double or triple bonds, each of which 1 to 8 carbon atomsmay be further substituted with one or more substituent(s) independentlyselected from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,and mono- or di-(C₁-C₄)alkylamino. R₁ and R₄, in this embodiment of theinvention, are independently selected from the group consisting ofhydrogen, halogen, C₁-C₄alkoxy, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, andC₁-C₆alkyl, which C₁₋₆alkyl is unsubstituted or substituted by one tothree substituents independently selected from hydroxy, oxo, cyano,C₁-C₄alkoxy, amino, and mono- or di(C₁-C₄)alkylamino.

R₃ is hydrogen, halogen, methyl, or methoxy.

R₅, R₆, and R₇ are independently selected from hydrogen, halogen, cyano,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino, C₁-C₆alkyl,C₁-C₆alkoxy, (C₁-C₄alkoxy)C₁-C₄alkoxy, and mono- or di(C₁-C₄alkyl)amino.

Additionally the invention includes compounds and pharmaceuticallyacceptable salts of Formula IV

Ar, R₁, R₃, and R₄ carry the definitions set forth for Formula IA. R_(X)and R_(Y) are joined to form a saturated 5 to 7 memberedheterocycloalkyl ring containing 0 or 1 additional heteroatom selectedfrom N, O, and S, wherein said saturated 5 to 7 memberedheterocycloalkyl ring is optionally substituted with from 1 to 4 groupsindependently chosen from halogen, hydroxy, methyl and methoxy.

A further embodiment of the invention includes compounds andpharmaceutically acceptable salts of Formula V

R_(X) and R_(Y) carry the definitions set forth for Formula II.

Ar, for compounds of Formula V, is phenyl or pyridyl, each of which ismono-, di-, or tri-substituted with R_(A) (which carries the definitionset forth for Formula IA), with the proviso that at least one of thepositions ortho to the point of attachment of Ar shown in Formula V issubstituted.

R₁ and R₄ are independently selected from the group consisting ofhydrogen, halogen, C₁-C₄alkoxy, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy,C₁-C₄alkyl, and mono- and di-(C₁-C₄alkyl)amino.

R₉ is selected from straight or branched alkyl groups, cycloalkylgroups, and (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms andcontaining zero or more double or triple bonds, each of which 1 to 8carbon atoms may be further substituted with one or more substituent(s)independently selected from oxo, hydroxy, halogen, cyano, C₁-C₄alkoxy,amino, and mono- or di-(C₁-C₄)alkylamino.

A particular subset of compounds of Formula V which are included in theinvention, is described by Formula VI:

In the embodiment of the invention described by Formula VI, thevariables R_(X) and R_(Y) carry the definitions set forth for FormulaII, and R₁, R₄, and R₉ carry the definitions set forth for Formula V.

A is CH or N.

R₅, R₆, and R₇, in this embodiment of the invention, are independentlyi) hydrogen, halogen, cyano, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy,hydroxy, amino, C₁-C₆alkyl, C₁-C₆alkoxy, (C₁-C₄alkoxy)C₁-C₄alkoxy, ormono- or di(C₁-C₄alkyl)amino, or ii) C₁-C₆alkyl or C₁-C₆alkoxy, each ofwhich is further substituted with a 3- to 7-membered carbocyclic orheterocyclic groups which is saturated, partially unsaturated, oraromatic, which may be further substituted with one or more substituentsindependently selected from halogen, oxo, hydroxy, amino, cyano,C₁-C₄alkyl, C₁-C₄alkoxy, and mono- or di-(C₁-C₄alkyl)amino.

In this embodiment at least one of R₅ and R₇ is not hydrogen.

Another subset of compounds of Formula V which are included in theinvention, is described by Formula VII:

In this embodiment of the invention R_(X) and R_(Y) carry thedefinitions set forth for Formula II and R₁, R₃, and R₄ carry thedefinitions set forth for compounds of Formula V.

A is CH or N and q is an integer from 1 to 4.

G is hydrogen, hydroxy, C₁-C₄alkoxy, mono- or di(C₁-C₄alkyl)amino, or a3- to 7-membered carbocyclic or heterocyclic group which is saturated,partially unsaturated, or aromatic, which may be further substitutedwith one or more substituents independently selected from halogen, oxo,hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, mono- ordi-(C₁-C₄alkyl)amino and —S(O)_(n)(alkyl), wherein said 3- to 7-memberedheterocyclic group contains from 1 to 3 heteroatom(s) independentlyselected from N, O, and S, with remaining ring members being carbon, andn is 0, 1, or 2.

J and K are independently selected from hydrogen, halogen, cyano,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino, C₁-C₆alkyl,C₁-C₆alkoxy, (CV C₄alkoxy)C₁-C₄alkoxy, and mono- or di(C₁-C₄alkyl)amino.

The invention further includes compounds of Formula VIII

and the pharmaceutically acceptable salt thereof. In this embodiment ofthe invention, the variables Ar, R₁, R₃, and R₄ carry the definitionsset forth for Formula IA.

R_(X) is a straight or branched alkyl group, cycloalkyl group, or(cycloalkyl)alkyl group, having 1 to 8 carbon atoms and containing zeroor more double or triple bonds, each of which 1 to 8 carbon atoms may befurther substituted with one or more substituent(s) independentlyselected from: i) halogen, hydroxy, amino, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, and mono- or di(C₁-C₄alkyl)amino, h) 3- to 7-memberedcarbocyclic or heterocyclic groups which are saturated, partiallyunsaturated, or aromatic, which may be further substituted with one ormore substituents independently selected from halogen, hydroxy, amino,cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono- or di-(C₁-C₄alkyl)amino,wherein said 3- to 7-membered heterocyclic groups contain from 1 to 3heteroatom(s) independently selected from N, O, and S, with remainingring members being carbon.

Preferred compounds and salts of Formula VIII in those wherein:

Ar is phenyl or pyridyl, each of which is mono-, di-, or tri-substitutedwith R_(A) (which carries the definitions set forth for Formula IA),with the proviso that at least one of the positions ortho to the pointof attachment of Ar shown in Formula VIII is substituted.

X is independently selected at each occurrence from the group consistingof —CH₂—, —CHR_(D)—, —O—, —C(═O)—, —C(═O)O—, —NH—, —NR_(D)—, —C(═O)NH—,—C(═O)NR_(D)—, —NHC(═O)—, and —NR_(D)C(═O)—.

Y and Z are independently selected at each occurrence from: 3- to7-membered carbocyclic or heterocyclic groups which are saturated,partially unsaturated, or aromatic, which may be further substitutedwith one or more substituents independently selected from halogen, oxo,hydroxy, amino, cyano, C₁-C₄alkyl, —O(C₁-C₄alkyl), and —NH(C₁-C₄alkyl),—N(C₁-C₄alkyl)(C₁-C₄alkyl), wherein said 3- to 7-membered heterocyclicgroups contain from 1 to 3 heteroatom(s) independently selected from N,O, and S, with remaining ring members being carbon; and

R_(C) and R_(D), are the same or different, and are independentlyselected at each occurrence from: hydrogen, and straight, branched, andcyclic alkyl groups, and (cycloalkyl)alkyl groups, having 1 to 8 carbonatoms, and containing zero or one or more double or triple bonds, eachof which 1 to 8 carbon atoms may be further substituted with one or moresubstituent(s) independently selected from oxo, hydroxy, halogen, cyano,amino, C₁-C₆alkoxy, mono- or di-(C₁-C₄alkyl)amino, —NHC(═O)(C₁-C₆alkyl),—N(C₁-C₆alkyl)C(═O)(C₁-C₆alkyl), and Z.

Preferred values of R₁, R₃ and R₄ for compounds and salts of Formula IAinclude

i) hydrogen, ii)halogen, iii) C₁-C₄alkyl, iv) C₁-C₃alkoxy, v)(C₃-C₇cycloalkyl)C₀-C₃alkyl, iii) (C₃-C₇cycloalkyl)C₀-C₃alkoxy, vii)mono- or di-(C₁-C₃alkyl)amino, viii) C₁-C₃haloalkyl, and ix)C₁-C₃haloalkoxy, wherein each of iii, iv, v, vi, and vii isunsubstituted or substituted by 1-3 groups independently chosen fromhalogen, hydroxy, oxo, cyano, C₁-C₄alkoxy, amino, and mono- ordi-(C₁-C₄alkyl)amino.

The invention also includes preferred compounds and salts of FormulaVIII in which:

R_(X) is a straight or branched alkyl group, a cycloalkyl groups, or(cycloalkyl)alkyl group, having 1 to 8 carbon atoms and containing zeroor more double or triple bonds, each of which 1 to 8 carbon atoms may befurther substituted with one or more substituent(s) independentlyselected from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,and mono- or di-(C₁-C₄)alkylamino. Ar is phenyl or pyridyl, mono-, di-,or tri-substituted with substituents independently selected at eachoccurrence from halogen, cyano, nitro, halo(C₁-C₆)alkyl,halo(C₁-C₄)alkoxy, hydroxy, amino, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆)alkynyl, C₁-C₆cycloalkyl, (C₁-C₆cycloalkyl)C₁-C₆alkyl,C₁-C₆alkoxy; and mono- or di-(C₁-C₆alkyl)amino.

R₁, R₃ and R₄ are independently selected from the group consisting ofhydrogen, halogen, C₁-C₄alkyl, C₁-C₃alkoxy, (C₃-C₇cycloalkyl)C₀-C₃alkyl,(C₃-C₇cycloalkyl)C₀-C₃alkoxy, mono- or di-(C₁-C₃alkyl)amino,C₁-C₃haloalkyl, and C₁-C₃haloalkoxy.

Particularly preferred compounds of this class include those wherein:

R_(X) is a C₁-C₆alkyl, C₃-C₇cycloalkyl, or (C₃-C₇cycloalkyl) C₁-C₄alkylgroup.

Ar is phenyl or pyridyl, mono-, di-, or tri-substituted withsubstituents independently selected at each occurrence from halogen,halo(C₁-C₂)alkyl, halo(CV C₂)alkoxy, hydroxy, amino, C₁-C₃alkyl,C₁-C₂alkoxy, and mono- or di-(C₁-C₂alkyl)amino.

R₁ and R₄ are independently selected from the group consisting ofhydrogen, halogen, C₁-C₃alkyl, C₁-C₃alkoxy, mono- ordi-(C₁-C₃alkyl)amino, C₁-C₃haloalkyl, and C₁-C₃haloalkoxy; and R₃ ishydrogen, halogen, or methyl.

In yet another embodiment, the invention includes a subset of compoundsof Formula VIII, which are described by Formula IX:

In this embodiment, R_(X) carries the definition set forth for FormulaVIII, and R₁, R₃, and R₄ carry the definitions set forth for Formula IA.

A is CH or N.

R₅, R₆, and R₇ are independently i) hydrogen, halogen, cyano,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino, C₁-C₆alkyl,C₁-C₆alkoxy, (C₁-C₄alkoxy) C₁-C₄alkoxy, or mono- or di(C₁-C₄alkyl)amino,or ii) C₁-C₆alkyl or C₁-C₆alkoxy, each of which is further substitutedwith a 3- to 7-membered carbocyclic or heterocyclic groups which issaturated, partially unsaturated, or aromatic, which may be furthersubstituted with one or more substituents independently selected fromhalogen, oxo, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono-or di-(C₁-C₄alkyl)amino, wherein said 3- to 7-membered heterocyclicgroup contains from 1 to 3 heteroatom(s) independently selected from N,O, and S, with remaining ring members being carbon. At least one of R₅and R₇ is not hydrogen.

Preferred compounds and salts of Formula IX include those wherein:

R_(X) is a straight or branched alkyl group, a cycloalkyl group, or(cycloalkyl)alkyl group, having 1 to 8 carbon atoms and containing zeroor more double or triple bonds, each of which 1 to 8 carbon atoms may befurther substituted with one or more substituent(s) independentlyselected from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,and mono- or di-(C₁-C₄)alkylamino.

R₁ and R₄ are independently selected from the group consisting ofhydrogen, halogen, C₁-C₄alkoxy, halo(C₁-C₄)alkyl, halo(C₁-C₄alkoxy, andC₁-C₆alkyl, which C₁₋₆alkyl is or substituted or substituted by one tothree substituents independently selected from hydroxy, oxo, cyano,C₁-C₄alkoxy, amino, and mono- or di(C₁-C₄)alkylamino.

R₃ is hydrogen, halogen, methyl, or methoxy.

R₅, R₆, and R₇ are independently selected from hydrogen, halogen, cyano,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino, C₁-C₆alkyl,C₁-C₆alkoxy, (C₁-C₄alkoxy)C₁-C₄alkoxy, and mono- or di(C₁-C₄alkyl)amino.

Other preferred values of R₁ for compounds and salts Formula IX, includehydrogen, halogen, methyl, ethyl, methoxy, ethoxy, and mono- anddi-(C₁-C₂alkyl)amino. Particularly preferred values of R₁ for compoundsand salts of Formula IX are methyl, ethyl, methylamino,methyl-ethyl-amino, methoxy and chloro.

Preferred R_(X) groups for Formula IX include straight or branched chainalkyl groups having 3 to 6 carbon atoms, particularly 1-ethyl-propyl.

For compounds of Formula IX it is also preferred that R₃ is hydrogen orchloro.

Preferred values of R₄ include methyl, ethyl, methoxy, ethoxy, andhalogen. Methyl, ethyl and bromo are particularly preferred.

In another preferred embodiment the invention includes compounds ofFormula IX in which R₁ is methylamino, R_(X) is -ethyl-propyl, R₃ ishydrogen or methyl, R₄ is methyl, ethyl or bromo, A is CH, R₅ and R₆,are selected from halogen, methoxy, ethoxy, methyl, ethyl, andtrifluoromethoxy, and R₇ is hydrogen or methyl.

In addition to compounds and salts of Formulae I-IX, above, theinvention provides compounds and pharmaceutically acceptable salts ofFormula X

A is a tetrahydropyridyl group or a piperidinyl group of Formula X-a,Formula X-b, or Formula X-c:

The position of substitution by the B group in the group represented byFormula X-a is the 4-position or 5-position, the position ofsubstitution by the G-(CH₂)_(n)— group in the group represented byFormula X-b is the 4-position or 5-position, and the position ofsubstitution the G-C(R₀)= group in the group represented by Formula X-cis the 3-position or 4-position.

In Formula X-a, B represents phenyl, pyridyl, pyrimidinyl, furanyl, orthiophenyl, each of which is unsubstituted or substituted by up to 3substituents independently selected from halogen, hydroxy, amino, cyano,alkyl, alkoxy, haloalkyl, and haloalkoxy.

D represents from 0 to 3 groups independently chosen from halogen,methyl, ethyl, methoxy, and ethoxy.

In Formula X-b, n is an integer of 0 to 5.

R₀, in Formula X-c, represents hydrogen, alkyl, cycloalkyl, or

(cycloalkyl)alkyl.

G represents i) cyano, ii) a group of the formula —CONR¹¹R₁₂ wherein R₁₁and R₁₂ are independently selected from hydrogen, alkyl, cycloalkyl,(cycloalkyl)alkyl, alkoxyalkyl, cycloalkyloxyalkyl, and phenyl, or R₁₁and R₁₂ are taken together with the nitrogen atom to which they areattached to form a 5- to 8-membered saturated heterocyclic group of theformula:

wherein E is CH₂, NH, N-alkyl, N-cycloalkyl, N-alkyl(cycloalkyl), O, orS, or iii) a group of the formula —CO₂R₁₃, wherein R₁₃, representshydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl,alkoxyalkyl(cycloalkyloxy)alkyl, or phenyl.

The variables Ar, R₁, R₃, and R₄ in Formula X carry the definitions setforth for Formula IA.

Preferred substituents of the Ar group, for compounds of Formula I,Formula IA and the subformulae thereof, including, for example,compounds of Formula II, Formula III, Formula VIII and Formula IX arechloro, methyl, methoxy, ethyl, ethoxy, trifluoromethoxy,difluoromethoxy, trifluoromethyl, difluoromethyl, 1-ethyl-propoxy,isopropoxy, isopropyl, and isopropyl amino. Particularly preferred Argroups, include, but are not limited to, 2,4-dimethoxyphenyl,2-methoxy-4-ethylphenyl, 2-methyl-4-methoxyphenyl,2-methoxy-4-trifluoromethoxyphenyl, 2,4-dichlorophenyl,2-chloro-4-methoxyphenyl, 2-methoxy-4-isopropoxyphenyl,2-chloro-4-isopropoxyphenyl, 2-methoxy-4-difluoromethoxyphenyl,2-methoxy-4-isopropylphenyl, 2-difluoromethoxy-4-methoxyphenyl,2-methoxy-4-trifluoromethoxyphenyl, 2-methoxy-4-ethoxyphenyl,2-methoxy-4-trifluoromethylphenyl, 2-trifluoromethoxy-4-methoxyphenyl,2-methoxy-4-isopropyl-3-pyridyl, 2-methoxy-4isopropyl-3-pyridyl,2-methoxy-4-isopropoxy-3-pyridyl, 2-methoxy-4-dimethylamino-3-pyridyl,4-isopropyl-6-methoxy-3-pyridyl, 4-isopropoxy-6-methoxy-3-pyridyl,4-isopropyl-6-methoxy-2-pyridyl, 2-ethyl-4-isopropyl-methoxy-3-pyridyl,2-methyl-4isopropylamino-5-methoxy-3pyridyl,2-hydroxymethyl-4-isopropyl-3-pyridyl, 2-ethoxy-4-isopropyl-3-pyridyl,2,4,6-trimethyl-5-(4-methyl-oxazol-2-yl)-3-pyridyl,2-ethyl-4-isopropyl-3-pyridyl, and 2-ethyl-4-isopropylaminophenyl.

Additional preferred Ar groups are given in the table entitled “ArMatrix” provided herein.

Preferred compounds of Formula I exhibit an IC₅₀ value of micromolar orless in a standard in vitro CRF receptor binding assay. More preferredcompounds exhibit an IC₅₀ value of 100 nanomolar or less in a standardin vitro CRF receptor binding assay. Particularly preferred compounds ofFormula I exhibit an IC₅₀ value of 10 nanomolar or less in a standard invitro CRF receptor binding assay. A standard in vitro CRF1 receptorbinding assay is disclosed in Example 11, below.

The invention further provides intermediates useful in the preparationof compounds of Formula I, Formula IA, any the particular embodimentsthereof (e.g., Formula II-Formula X), or any of the compounds of FormulaI specifically disclosed herein. Intermediates useful in the synthesisof compounds in the invention are described in Schemes 1-3 below, andfurther illustrated in Examples 1-7. For example, useful intermediatesprovided by the invention include aryl metallo compounds and arylboronic acids useful for coupling to the pyridine core of Formula I.Particular examples of such intermediates include, for example4-methoxy-2-methylbenzeneboronic acid,2-Methoxy-6-isopropyl-3-pyridylboronic acid (step 3, example 4), and4-Trifluoromethoxy-2-methoxy-phenylboronic acid (see step 6, example 5).

The invention also provides pharmaceutical compositions comprising acompound, pharmaceutically acceptable salt, or prodrug of Formula I,Formula IA, any the particular embodiments (hereof (e.g., FormulaII-Formula X), or any of the compounds of Formula I specificallydisclosed herein, together with a pharmaceutically acceptable carrier orexcipient. Pharmaceutically acceptable carriers suitable for use in acomposition provided by the invention may be inert, or may modulate thebioavailability or stability of the active compound. Representativecarriers include, for example, molecules such as albumin, polylysine,polyamidoamines, peptides, proteins, polystyrene, polyacrylamide,lipids, ceramide and biotin, solid support materials such as beads andmicroparticles comprising, for example, polyacetate, polyglycolate,poly(lactide-co-glycolide), polyacrylate, starch, cellulose or dextran.The pharmaceutical composition, may be prepared in a variety of forms,for example, as an injectable fluid, an aerosol, a cream, a gel, a pill,a capsule, a syrup, or a transdermal patch.

The invention also provides packages comprising a pharmaceuticalcomposition as described immediately above in a container andinstructions for using the composition to treat a patient suffering fromanxiety, or instructions for using the composition to treat a patientsuffering from stress, or instructions for using the composition totreat a patient suffering from depression, or instructions for using thecomposition to treat a patient suffering from irritable bowel syndromeor instructions for using the composition to treat a patient sufferingfrom Crohn's disease.

The CRF binding compounds provided by this invention and labeledderivatives thereof are also useful as standards and reagents indetermining the ability of other compounds (e.g., a potentialpharmaceutical agent) to bind to the CRF receptor.

The invention provides a method for demonstrating the presence of CRFreceptors (preferably CRF1 receptors) in a biological sample (e.g., atissue section or homogenate), said method comprising contacting thebiological sample with a labeled compound of Formula I under conditionsthat permit binding of the labeled compound to a CRF receptor anddetecting the labeled compound in the biological sample. Unbound labeledcompound is preferably at least partially removed from the biologicalsample prior to detecting the bound labeled compound in the sample.

For detection purposes the compound may be labeled, for example, with afluorescent, isotopic, or radiolabel. Radiolabeled and isotopicallylabeled compounds of Formula I-X, which are also included in theinvention, are identical to the compounds recited in Formulae I-X, withone or more atoms replaced by an atom having an atomic mass or massnumber different from the most highly abundant isotope of that atom.Examples of isotopes that can be incorporated into compounds of FormulaI in accordance with this aspect of the invention includes isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, 3H, ¹¹C, 13C, 14C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P ³²P, ³⁵S, 35F, and18F, and ³⁶Cl. Preparation of such radiolabeled compounds of Formula Iis described below in Example 12. The labeled compound may be detectedif radiolabeled, e.g., autoradiographically, and if otherwiseisotopically labeled, e.g., by NMR. Labeled derivatives of the CRFantagonist compounds of Formula I are also useful as radiotracers forpositron emission tomography (PET) imaging or for single photon emissioncomputerized tomography (SPECT).

The present invention also pertains to methods of inhibiting the bindingof CRF to CRF receptors which methods involve contacting a solutioncontaining a compound of Formula I with at least one cell (e.g., aneuronal cell) expressing CRF receptors (e.g., preferably CRF1receptors), wherein the compound is present in the solution at aconcentration sufficient to inhibit CRF binding to CRF receptors invitro. This method includes inhibiting the binding of CRF to CRFreceptors in vivo in an animal (e.g., preferably a human patient). Theanimal is given an amount of a compound of Formula I that results in aconcentration in a relevant body fluid (e.g., blood, plasma, serum, CSF,interstitial fluid) of the animal, which concentration is at leastsufficient to inhibit the binding of CRF to CRF receptors in vitro.

The present invention also pertains to methods of altering (i.e.increasing or decreasing) the CRF-stimulated activity of CRF receptors,which methods involve contacting a solution containing a compoundFormula I with at least one cell (e.g., a neuronal cell) expressing CRFreceptors (e.g., preferably CRF1 receptors), wherein the compound ispresent in the solution at a concentration sufficient to alter theCRF-stimulated signal transduction activity of CRF receptors in cellsexpressing CRF receptors (preferably cells expressing such receptors atlevels above those found in naturally occurring CRF receptor-expressingcells) in vitro. This method includes altering the CRF-stimulatedactivity of CRF receptors in vivo in an animal (e.g., preferably a humanpatient). The animal is given an amount of a compound of Formula I thatresults in compound a concentration in a relevant body fluid (e.g.,blood, plasma, serum, CSF, interstitial fluid) of the animal, whichconcentration is at least sufficient to alter the CRF-stimulatedactivity of CRF receptors in vitro.

In one embodiment, such methods are useful in treating physiologicaldisorders associated with excess concentrations of CRF in a patient(e.g., in a body fluid of the patient). The amount of a compound thatwould be sufficient to inhibit the binding of a CRF to a CRF receptor orto alter the CRF-stimulated activity of CRF receptors may be readilydetermined via a CRF receptor binding assay (see Example 11), or fromthe EC₅₀ of a CRF receptor functional assay. CRF receptors that may beused to determine in vitro binding are found in a variety of sources,for example in cells that autologously express CRF receptors, e.g. IMR32cells, or in a cell expressing a CRF receptor as a result of theexpression of an exogenous CRF receptor-encoding polynucleotidecomprised by the cell.

Methods of Treatment

Compounds of Formula I are useful in treating a variety of conditionsincluding affective disorders, anxiety disorders, stress disorders,eating disorders, digestive disorders, and drug addiction.

Affective disorders include all types of depression, bipolar disorder,cyclothymia, and dysthymia.

Anxiety disorders include generalized anxiety disorder, panic, phobiasand obsessive-compulsive disorder.

Stress, includes, for example, post-traumatic stress disorder,hemorrhagic stress, stress-induced psychotic episodes, psychosocialdwarfism, stress headaches, stress-induced immune systems disorders suchas stress-induced fever, and stress-related sleep disorders.

Eating disorders include anorexia nervosa, bulimia nervosa, and obesity.

Digestive disorders include, but are not limited to irritable bowelsyndrome and Crohn's disease.

Modulators of the CRF receptors may also be useful in the treatment of avariety of neurological disorders including supranuclear palsy, AIDSrelated dementias, multiinfarct dementia, neurodegenerative disorderssuch as Alzheimer's disease, Parkinson's disease, and Huntington'sdisease, head trauma, spinal cord trauma, ischemic neuronal damage,amyotrophic lateral sclerosis, disorders of pain perception such asfibromyalgia and epilepsy.

Additionally compounds of Formula I are useful as modulators of the CRFreceptor in the treatment of a number of gastrointestinal,cardiovascular, hormonal, autoimmune and inflammatory conditions. Suchconditions include ulcers, spastic colon, diarrhea, post operative iliusand colonic hypersensitivity associated with psychopathologicaldisturbances or stress, hypertension, tachycardia, congestive heartfailure, infertility, euthyroid sick syndrome, inflammatory conditionseffected by rheumatoid arthritis and osteoarthritis, pain, asthma,psoriasis and allergies.

Compounds of Formula I are also useful as modulators of the CRF1receptor in the treatment of animal disorders associated with aberrantCRF levels. These conditions include porcine stress syndrome, bovineshipping fever, equine paroxysmal fibrillation, and dysfunctions inducedby confinement in chickens, sheering stress in sheep or human-animalinteraction related stress in dogs, psychosocial dwarfism andhypoglycemia.

Typical subjects to which compounds of Formula I may be administeredwill be mammals, particularly primates, especially humans. Forveterinary applications, a wide variety of subjects will be suitable,e.g. livestock such as cattle, sheep, goats, cows, swine and the like;poultry such as chickens, ducks, geese, turkeys, and the like; anddomesticated animals particularly pets such as dogs and cats. Fordiagnostic or research applications, a wide variety of mammals will besuitable subjects including rodents (e.g. mice, rats, hamsters),rabbits, primates, and swine such as inbred pigs and the like.Additionally, for in vitro applications, such as in vitro diagnostic andresearch applications, body fluids and cell samples of the abovesubjects will be suitable for use such as mammalian, particularlyprimate such as human, blood, urine or tissue samples, or blood urine ortissue samples of the animals mentioned for veterinary applications.

Pharmaceutical Preparations

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrathecal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired, other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a lime delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol substitute, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan substitute.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example peanut oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or peanut oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, or flavoring or coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents that have been mentioned above. Thesterile injectable preparation may also be sterile an injectablesolution or suspension in a non-toxic parentally acceptable dilutent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most CNSdisorders, a dosage regimen of 4 times daily or less is preferred. Forthe treatment of stress and depression a dosage regimen of 1 or 2 timesdaily is particularly preferred.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preferred compounds of Formula I will have certain pharmacologicalproperties. Such properties include, but are not limited to oralbioavailability, optimal volume of distribution, low toxicity, low serumprotein binding, and desirable in vitro and in vivo half-lifes.Penetration of the blood brain barrier for compounds used to treat CNSdisorders is necessary, while low brain levels of compounds used totreat periphereal disorders are often preferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocycles may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcová, et al. (Journal ofChromatography B (1996) volume 677, pages 1-27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lives of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

As discussed above, preferred arylpyridines of Formula I exhibitactivity in standard in vitro CRF receptor binding assays, specificallythe assay as specified in Example 11, which follows. References hereinto “standard in vitro receptor binding assay” are intended to refer tothat protocol as defined in Example 13 which follows. Generallypreferred arylpyridines of Formula I have an IC₅₀ of about 1 micromolaror less, still more preferably and IC₅₀ of about 100 nanomolar or lesseven more preferably an IC₅₀ of about 10 nanomolar or less or even 1nanomolar or less in such a defined standard in vitro CRF receptorbinding assay as exemplified by Example 11 which follows.

EXAMPLES Preparation of 5-Substituted-2-Arylpyridines

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include but are not limitedto those methods described below. Each of the references cited below arehereby incorporated herein by reference for their teaching regarding thesynthesis of arylpyridine compounds. Preferred methods for thepreparation of compounds of the present invention include, but are notlimited to, those described in Scheme I to Scheme V. Those who areskilled in the art will recognize that the starting materials may bevaried and additional steps employed to produce compounds encompassed bythe present invention. The following abbreviations are used herein:

-   Bz benzyl-   Cmp# Compound number-   DPPA diphenylphosphoryl azide-   DME dimethyl ethane-   DMF dimethyl formamide-   EtOAc Ethyl Acetate-   Fe(acac)₃ Iron tri-acetylacetonate-   M-CPBA m-chloroperoxybenzoic acid-   NaBH(OAc)₃ Sodium triacetoxyborohydride-   NMP N-methylpyrrolidinone-   Pd/C Palladium carbon catalyst-   Pd₂ dba₃ Tris(dibenzylideneacetone)-dipalladium(0)-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium-   P(t-Bu)₃ tri-t-butyl phosphate-   SPE Column Solid-phase extraction column-   t-BuOK Potassium tertiary butoxide-   Tf₂0-Triflic anhydride

Selective metal catalyzed cross couplings of the 2,5-dihalopyridineafford 5-halo-2-arylpyridines 1. The desired 3-alkoxy-6-arylpyridine 2is obtained by heating the 5-halo-2-arylpyridines with alkoxide. The3-alkoxy-6-arylpyridine 2 is converted to the N-oxide in m-CPBA at roomtemperature. The intermediate, 2-halo-3-alkoxy-6-arylpyridine 4, is thenobtained from the N-oxide 3 by heating in POCl₃, Conversion of the2-halopyridine provides the compounds, for example2,3-dialkoxy-6-arylpyridine 5 by nucleophilic substitution,2-alkyl-3-alkoxy-6-arylpyridine 6 by cross coupling and2-amino-3-alkoxy-6-arylpyridine 7 by amination.

3-Alkoxypyridines are also synthesized by alkylation of 3-pyridinols bythe method shown in Scheme II. Starting with 2-aminopyridine 8,nitration of the 5-position, followed by hydroxy dediazatization yields2-pyridinol 9 which is further converted to 2-chloropyridine 10 Crosscoupling of the resulting chloride gives the appropriate 6-arylpyridine12, which is reduced to 5-aminopyridine 13 by hydrogenation. Hydroxydediazatization gives the desired 3-pyridinol 14. Alkylation of 14provides the target 3-alkoxy-6-arylpyridine compounds 16.

Arylpyridines may also be synthesized by construction of the pyridinering as shown in Scheme III. Condensation of malonic acids with aminesgives dihydroxypyridine 19 which is easily converted into2,4-dichloropyridine 20. Selective cross coupling is achieved to afford2-aryl-4-chloropyridine 21. R₃ is introduced by simple substitution togive 22 which is then hydrolyzed to afford the acid 23. Curtiusrearrangement, followed by protection of the aniline gives arylpyridine24. Alkylation of the amide is followed by deprotection and reductivealkylation to give the target compounds 27.

Alternatively, 2-amino-3-alkoxy-6-arylpyridines are synthesized from2-halo-3-pyridinols as shown in Scheme IV. Iodination of2-halo-3-pyridinol 28 gives 2-halo-6-iodo-3-pyridinol, which is easilyalkylated to afford the corresponding 3-alkoxypyridines. By carefullyapplying chemoselectivity between 2-halo and 6-iodo, amination isachieved exclusively at the 2-position of the pyridine to afford2-amino-3-alkoxy-6-iodopyridine 31. Further halogenation introduces5-halo substituted pyridines 32. By metal catalyzed cross coupling, arylsubstitutents are regioselectively introduced at the 6-position of thepyridine. Another step of cross coupling yields the target compounds 34.

Furthermore, as shown in Scheme V, starting from 3-halo-5-pyridinol,2,5-dialkyl-3-alkoxy-6-arylpyridines are synthesized in six steps.Alkylation of the pyridinol 35 gives 3-halo-5-alkoxypyridines 36, whichundergo metal catalyzed cross coupling to give 3-alkoxy-5-alkylpyridine37. Halogenation of the 2-position of pyridine ring give2-halo-3-alkoxy-5-alkylpyrine. Cross coupling of the resulting2-halo-3-alkoxy-5-alkylpyrine 38 yields 2,3,5-tristibstituted pyridine39. Halogenation of 39, followed by metal catalyzed cross coupling givetarget pyridine derivative 41.

The preparation of the compounds of the present invention is illustratedfurther by the following examples, which are not to be construed aslimiting the invention in scope or to the specific procedures andcompounds described in them.

Commercial reagents are used without further purification. Room orambient temperature refers to 20 to 25° C. Concentration in vacuoimplies the use of a rotary evaporator. TLC refers to thin layerchromatography. Silica gel is used for purification of reaction productsby column chromatography. Proton nuclear magnetic resonance (¹H NMR)spectral data are obtained at 300 or 400 MHz in CDCl₃, and reported asppm, unless otherwise stated. Mass spectral data are obtained either byCI or APCI methods.

Example 1 Preparation of3-Methyl-5-(1-ethyl-propoxy)-2-(2-methoxy-4-trifluoromethoxy-phenyl)-6-ethyl-pyridineand3-methyl-5-(1-ethyl-propoxy)-2-(2-methoxy-4-trifluoromethoxy-phenyl)-6-methylamino-pyridine

Step 1. 5-Bromo-2-(2-methoxy-4-trifluoromethoxyphenyl)-3-methylpyridine(42)

Pd(PPh₃)₄ (1.15 g, 0.996 mmol) is added to a solution of2,5-dibromo-3-methylpyridine (10 g, 39.85 mmol) in toluene (100 ml),followed by the addition of 2-methoxy-4-trifluorormethoxyphenylboronicacid (9.6 g, 39.85 mmol) and Na₂CO₃ (1M, 50 ml, 50 mmol). The resultingmixture is heated to reflux overnight, and then cooled to roomtemperature. The toluene layer is separated. The aqueous layer isextracted with EtOAc. The organic layers are combined, washed withwater, brine, dried, filtered, and evaporated. The crude product ispurified by chromatography (eluted with 6% EtOAc in hexane) to give theproduct as colorless oil. ¹H NMR (CDCl₃) δ 2.14 (s, 3H), 3.77 (s, 3H),6.81 (s, 1H), 6.92 (dd, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.72 (s, 1H), 8.56(s, 1H). LCMS 362, 364 (M+1).

Step 2.5-(1-Ethylpropoxy)-2-(2-methoxy-4-trifluoromethoxyphenyl)-3-methylpyridine(43)

Compound 42 (3.62 g, 10 mmol) is added to a solution of sodium3-pentoxide in NMP (1M, 30 ml, 30 mmol). The resulting mixture is heatedto 120° C. for 2.5 h, and then cooled to room temperature, diluted with50% EtOAc in hexane, washed with water, brine, dried, filtered andevaporated. The crude product is purified by chromatography (eluted with6% EtOAc in hexane) to give the product as colorless oil. ¹H NMR (CDCl₃)δ 0.98 (t, J=7.6 Hz, 6H), 1.72 (m, 4H), 2.15 (s, 3H), 3.77 (s, 3H), 4.17(m, 1H), 6.79 (s, 1H), 6.91 (dd, 1H), 7.07 (d, J=1.6 Hz, 1H), 7.27 (d,J=8.4 Hz, 1H), 8.18 (d, J=1.6 Hz, 1H). LCMS 370.2 (M+1).

Step 3.5-(1-Ethylpropoxy)-2-(2-methoxy-4-trifluoromethoxyphenyl)-3-methylpyridine-1-oxide(44)

M-CPBA (314 mg, 77%, 1.4 mmol) is added to a solution of compound 43(410 mg, 1.11 mmol) in CH₂Cl₂ (5 ml). The resulting solution is stirredat room temperature for 3 hours, and then evaporated to dryness. Theresidue is dissolved in EtOAc, washed with Na₂CO₃ (1 M), water, brine,dried, filtered and evaporated. The crude product is purified bychromatography (eluted with EtOAc) to give the product as a whitecrystalline solid. ¹H NMR (CDCl₃) δ 0.97 (t, J=7.6 Hz, 6H), 1.71 (m,4H), 2.02 (s, 3H), 3.79 (s, 3H), 4.09 (m, 1H), 6.78 (d, J=1.2 Hz, 1H),6.84 (s, 1H), 6.92 (dd, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.95 (d, J=1.2 Hz,1H). LCMS 386 (M+1).

Step 4. Preparation of2-Chloro-3-(1-ethylpropoxy)-6-(2-methoxy-4-trifluoromethoxyphenyl)-5-methylpyridine(45)

A solution of compound 44 (340 mg, 0.88 mmol) in POCl₃ (0.4 ml) isstirred at 65° C. for 1 hour, then cooled to room temperature and pouredonto ice (10 g). The resulting solution is neutralized with Na₂CO₃, andextracted with 50% EtOAc in hexane. The combined extracts are washedwith water, brine, dried, filtered and evaporated. The crude product ispurified by chromatography (eluted with 6% EtOAc in hexane) to give theproduct as a w hue crystalline solid, ¹H NMR (CDCl₃) δ 1.01 (t, J=7.6Hz, 6H), 1.76 (m, 4H), 2.12 (s, 3H), 3.78 (s, 3H), 4.19 (m, 1H), 6.78(s, 1H), 6.89 (dd, 1H), 7.05 (s, 1H), 7.26 (s, 1H), 7.27 (d, J=8.4 Hz,1H). LCMS 404.27 (M+1).

Step 5.2-Methoxy-3-(1-ethylpropoxy)-6-(2-methoxy-4-trifluoromethoxyphenyl)-5-methylpyridine(46)

Sodium methoxide in methanol (25 w/w %, 0.5 ml) is added to a solutionof compound 45 (50 mg, 0.124 mmol) in NMP (0.5 ml). The resultingmixture is heated to 100° C. overnight, then cooled to room temperature,diluted with 50% EtOAc in hexane, washed with water, brine, dried,filtered and evaporated. The crude product is purified by chromatography(eluted with 6% EtOAc in hexane) to give the product as colorless oil.¹H NMR (CDCl₃) δ 1.00 (t, J=7.6 Hz, 6H), 1.75 (m, 4H), 2.04 (s, 3H),3.80 (s, 3H), 3.94 (s, 3H), 4.12 (m. 1H), 6.78 (s, 1H), 6.89 (dd, 1H),6.92 (s, 3H), 7.30 (d, J=8.4 Hz, 1H). LCMS 400.4 (M+1).

Step 6.2-Ethyl-3-(1-ethylpropoxy)-6-(2-methoxy-4-trifluoromethoxyphenyl)-5-methylpyridine(47)

Pd(PPh₃)₄ (12 mg, 0.01 mmol) is added to a solution of compound 45 (41mg, 0.1 mmol) in toluene (0.6 ml), followed by ethylboronic acid (73 mg,1 mmol) and Na₂CO₃ (1 M, 0.2 ml, 0.2 mmol). The resulting mixture ishealed to reflux overnight, and then cooled to room temperature. Thetoluene layer is separated. The aqueous layer is extracted with EtOAc.The combined organic layers are combined, washed with water, brine,dried, filtered and evaporated. The crude product is purified bychromatography (eluted with 6% EtOAc in hexane) to give the product as awhite crystalline solid. ¹H NMR (CDCl₃) δ 1.00 (t, J=7.6 Hz, 6H), 3.23(t, J=7.6 Hz, 3H), 1.73 (m, 4H), 2.09 (s, 3H), 2.84 (q, J=7.6 Hz, 2H),3.87 (s, 3H), 4.16 (m, 1H), 6.78 (s, 1H), 6.89 (dd, 1H), 6.92 (s, 1H),7.27 (d, J=8.4 Hz, 1H). LCMS 398.34 (M+1).

Step 7.[3-(1-Ethylpropoxy)-6-(2-methoxy-4-trifluoromethoxyphenyl)-5-methylpyridin-2-yl]-methylamine(48)

Pd₂ dba₃ (4 mg) is added to a solution of compound 45 (70 mg, 0.173mmol) in toluene (1 ml), followed by the addition of P(t-Bu)₃ (1.4 mg),methylamine (2M in THF, 0.17 ml, 0.347 mmol) and t-BuOK (1M in THF, 0.26ml, 0.26 mmol). The resulting mixture is sealed and heated to 55° C.overnight, then cooled to room temperature. The reaction mixture isdiluted with 30% EtOAc in hexane, washed with water, brine, dried,filtered and evaporated. The crude product is purified by chromatograph(eluted with 6% EtOAc in hexane) to give the product 48 as a lightyellow solid. ¹H NMR (CDCl₃) δ 0.97 (t, J=7.6 Hz, 6H), 1.71 (m, 4H),1.98 (s, 3H), 2.99 (s, 3H), 3.79 (s, 3H), 4.13 (m, 1H), 4.77 (brs, 1H),6.67 (s, 1H), 6.77 (s, 1H), 6.87 (dd, 1H), 7.32 (d, J=8.4 Hz, 1H). LCMS399.4 (M+1).

Example 2 Preparation of3-Ethyl-5-(1-ethyl-propoxy)-2-(2-methoxy-4-trifluoromethoxy-phenyl)-6-methyl-pyridine

A solution of NaNO₂ (2.1 g) in water (3.8 ml) is added drop-wise over 3hours, at 30 degrees C., to a mixture containing compound 49 (4.2 g)dissolved in concentrated sulfuric acid (7.6 ml), or alternativelyconcentrated nitric acid, and water (5.7 ml). The mixture is then heatedto 80 degrees C. for 1 hour, cooled to room temperature, diluted withwater (about 20 ml) and filtered to give pale yellow solid, 50. MS, 181(M−H).

A mixture of POCl₃ (3.8 ml), PCl₅ (7.5 g) and compound 50 (4.3 g) isheated to 110 degrees C. for 5 hours. After cooling to room temperature,the mixture is poured into ice-water. Solids are filtered and theaqueous filtrate is extracted with ether. The ether extract isconcentrated and purified by flash chromatography to give yellow oil,51. NMR, 8.19(s, 1H), 2.82 (s, 3H), 2.81 (q, 2H), 1.30(t, 3H).

Compound 51 (201 mg) is combined with2-methoxy-4-trifluoromethoxybenzeneboronic acid (248 mg) and aqueoussodium carbonate (1M, 2.8 ml) in DME (5.6 ml). The mixture is degassedby bubbling in nitrogen gas for 1 minute. Fresh Pd(PPh₃)₄ (48 mg) isadded. The mixture is heated to 80 degrees C. for 6 hours, then pouredinto water and extracted with, toluene. The extract is concentrated andpurified by flash chromatography, with 10% ethyl acetate in hexanes aseluant, to give yellow oil, 53 (200 mg). NMR, 8.22(s, 1H), 7.27 (d, 1H),6.95 (d, 1H), 6.83 (s, 1H), 3.78 (s, 3H), 2.86 (s, 3H), 2.51 (b, 2H),1.14(t, 3H).

Compound 53 (180 mg) is dissolved in methanol (10 ml) containing 10%Pd/C (10 mg) and hydrogenated at 40 psi with a Parr shaker. The solutionis filtered and concentrated to give 54, which can be subsequently usedwithout further purification. MS, 327 (M+1).

Compound 54 (203 mg) is dissolved in a solution of concentrated sulfuricacid (70 microliters) and water (0.6 ml), cooled to 0 degrees C., andtreated by drop-wise addition of NaNO₂ (59 mg) in water (0.5 ml). Themixture is stirred for 8 hours at room temperature, basified with NaHCO₃(5 ml) and extracted with ethyl acetate. The extract is concentrated togive yellow solid, 55. MS, 328 (M+1).

NaH (60%, 57 mg) is added to compound 55 (200 mg) dissolved in NMP (2.5ml). After gas evolution ceases, 3-bromopentane (56) is added and themixture is stirred at 85 degrees C. for 5 hours. The mixture is intowater and extracted with ethyl acetate. The product is purified andconcentrated by preparative TLC using 20% ethyl acetate in hexanes aseluant to give compound 57. MS, 398 (M+H); NMR, 7.24(d, 1H), 6.95 (s,1H), 6.89 (d, 1H), 6.77 (s, 1H), 4.16 (m, 1H), 3.76 (s, 3H), 2.43 (s,3H), 2.39 (m, 2H), 2.74 (m, 4H), 1.06 (t, 3H), 0.99 (t, 6H).

Example 3 Preparation of[5-Ethyl-6-(2-methyl-4-methoxy-phenyl)-2-methyl-pyridin-3-yl]-dipropyl-amine

A mixture of compounds 58 (2.6 g) and 59 is heated to 105 degrees C. for1.5 hours in acetic anhydride (30 ml) (Procedure given in J. Prakt.Chem., 82, 619). The mixture is concentrated, dissolved in NaOH (4N, 100ml), heated to 100 degrees C. for 1.5 hours, cooled and acidified to pH4. The precipitate is filtered and dried to give 60.

Compound 60 (4 g) is heated to 100 degrees C. for 8 hours in POCl₃ (20ml) and Mc₄NCl (4 g). The mixture is concentrated, diluted with waterand extracted with ether/hexanes. The extract is concentrated to give 61as a colorless oil.

Compound 61 (200 mg), 4-methoxy-2-methylbenzeneboronic acid, and aqueoussodium carbonate (1M, 2.5 ml) in DME (5.5 ml) are combined. The mixtureis degassed by bubbling in nitrogen gas for 1 minute followed byaddition of fresh Pd(PPh₃)₄ (30 mg). The mixture is heated to 80 degreesC. for 1 hour, poured into water, and extracted with toluene. Theextract is concentrated and purified by flash chromatography, with 20%ethyl acetate in hexanes as eluant, to give compound 62 (200 mg).

A mixture of compound 62 (200 mg). HCO₂ ⁻NH₄ ⁺ (400 mg) and 10% Pd/C (20mg) is refluxed in methanol (5 ml) for 2 hours. The mixture is filteredand concentrated to give compound 63.

Compound 63 (0.5 g) is dissolved in NaOH (1M, 5 ml) and methanol (5 ml),and heated to reflux for 8 hours. After cooling, the solution is dilutedwith water, acidified to pH 3 and extracted with dichloromethane. Theextract is concentrated to give compound 64.

Compound 64 (150 mg) is dissolved in a mixture of toluene (2 ml)containing diisopropylethylamine (0.2 ml) and DPPA (0.17 ml). Thesolution is stirred for 1.5 hours at room temperature, then heated to100 degrees C. for 10 minutes to purge nitrogen. Allyl alcohol (0.2 ml)is then added and the heating continued for 0.5 hour. The reactionmixture is cooled, diluted with water, extracted with toluene,concentrated and purified by flash chromatography to give compound 65.

Sodium hydride (60%, 50 mg) is added to a solution of compound 65 (140mg) in dimethylformamide (2 ml). After stirring at room temperature for5 minutes, iodopropane (60 microliters) is added. Stinting is continuedfor 0.5 hour. The mixture is diluted with water, extracted with toluene,concentrated and purified through an SPE column with hexanes/ether togive compound 66.

Pd(PPh₃)₄ (25 mg) is added to a solution of compound 66 (180 mg) indichloromethane (2 ml) and morpholine (100 microliter). The mixture isstirred at room temperature for 0.5 hour and filtered through an SPEcolumn to give compound 67 as a colorless oil.

A mixture of compound 67 (0.07 mmole), propanal (0.14 mmole) andNaBH(OAc)₃ (0.21 mmole) in dichloroethane (1 ml) is heated to 40 degreesC. for 24 hours. The mixture is quenched with sodium hydroxide (1N, 2drops), stirred vigorously and filtered though an SPE column to givecompound 68 MS 341M(M+H). NMR 7.24(s, 1H), 7.11 (d, 1H), 6.79 (s, 1H),6.77 (d, 1H), 3.82 (s, 3H), 2.96 (q, 4H), 2.51 (s, 3H), 2.35 (q, 2H),2.08 (s, 3H), 1.49 (m, 4H), 1.03 (t, 3H), 0.90 (t, 6H).

Example 4 Preparation of[3,2′-Diethyl-5-(1-ethyl-propoxy)-6′-isopropyl-[2,3′]bipyridinyl-6-yl]-methyl-amine(36) and[2″-Ethoxy-3-ethyl-5-(1-ethyl-propoxy)-6′-isopropyl-1′2′-Dihydro-[2,3′]bipyridinyl-6-yl]-methyl-amine(34)

Step 1. Preparation of[3-(1-ethyl-propoxy)-6-iodo-pyridin-2-yl]-methyl-amine

I₂ (45.8 g, 0.18 mol) is added to a solution of 2-chloro-3-pyridinol(69, 23.4 g, 0.18 mol) in Na₂CO₃ (225 ml, 1.0M aqueous solution, 0.225mol). The I₂ initially remains in the bottom of the flask but dissolveswith stirring overnight. The solution becomes lighter in color dark anda white solid precipitates. The mixture is then diluted with EtOAc andacidified with concentrated HCl to pH 2-3. The solution is extractedwith EtOAc. The combined extracts are washed with H₂O, dried, evaporatedto give the 2-chloro-5-iodo-3-pyridinol as a yellow solid.

The solid is dissolved in DMF (300 ml). Solid K₂CO₃ (40 g) and3-bromopentane (44.8 ml, 2 eq) are added to this solution. The resultingmixture is heated to 90° C. with gentle reflux for 2-4 hrs, then cooledto room temperature, poured into 5% EtOAc/hexane, washed with H₂Oseveral times, and dried. The solvent is removed to give an oil which isused without further purification in die next step.

The above oil (40 g) is dissolved in CH₃NH₂ (4N in NMP, 85 ml, 3 eq),sealed, and heated to 100° C. for 2 days. The mixture is then dilutedwith 5% EtOAc in hexane, washed with H₂O several times and dried.Solvent is removed to give a dark green oil. Crystals formed on cooling.The mixture of oil and crystals is filtered. The solid is washed withhexane and dried to give compound 70 as light green crystalline solid.The filtrate was collected to give an oil which is purified by columnchromatography (3% EtOAc/hexane) to give additional solid product([3-(1-ethyl-propoxy)-6-iodo-pyridin-2-yl]-methyl-amine). MS 321.2(M+1). ¹H NMR (CDCl₃) δ ppm 0.92 (t, 6H), 1.65 (m, 4H), 2.98 (d, 3H),4.04 (m, 1H), 4.94 (brs, 1H), 6.43 (d, 1H), 6.82 (d, 1H).

Step 2. Preparation of[3-(1-ethyl-propoxy)-5-bromo-6-iodo-pyridin-2-yl]-methyl-amine

NBS (11.67 g, 65.59 mmol) is added to a solution of 70 (20 g, 62.47mmol) in CHCl₃ (240 ml) at 0° C., warmed to room temperature, stirredfor 20 minutes, and then evaporated to remove the CHCl₃. 6% EtOAc inhexane is added to the residue and washed with saturated NaHCO₃, H₂O,dried, and evaporated. The crystals which form are collected byfiltration. The solid is washed with hexane and dried to give compound71 as light brown solid. The filtrate is then purified by column (1%EtOAc in hexane) to provide additional product. MS 399.2, 401.2 (M+1).¹H NMR (CDCl₃) δ ppm 0.92 (t, 6H), 1.67 (m, 4H), 2.98 (d, 3H), 4.06 (m,1H), 4.94 (brs, 1H), 6.84 (s, 1H).

Step 3. Preparation of[3-bromo-5-(1-ethyl-propoxy)-2′-Methoxy-6′-isopropyl-[2,3′]bipyridinyl-6-yl]-methyl-amine

Pd(PPh₃)₄ (2.5 Mol %) is added to a solution of compounds 71 in DME. Themixture is stirred at room temperature for 20 minutes.2-Methoxy-6-isopropyl-3-pyridylboronic acid (1.9 g, 9.74 mmol) is added,followed by Na₂CO₃ (17.7 ml, 1M, 17.7 mmol). The resulting mixture isheated to reflux overnight. After cooling to room temperature, themixture is diluted with 30% EtOAc in hexane, and then washed with H₂Oand brine. The crude is purified by column chromatography (eluted with4% EtOAc in hexane) to give compound 72 as white crystalline solid. MS422.3, 424.3 (M+1). ¹H NMR (CDCl₃) δ ppm 0.96 (t, 6H), 1.30 (d, 6H),1.71 (m, 4H), 2.97 (m, 1H), 2.98 (d, 3H), 3.96 (s, 3H), 4.12 (m, 1H),4.94 (brs, 1H), 6.80 (d, 1H), 6.96 (s, 1H), 7.50 (d, 1H).

Step 4. Preparation of[3-ethyl-5-(1-ethyl-propoxy)-2′-Methoxy-6′-isopropyl-[2,3′]bipyridinyl-6-yl]-methyl-amine

Pd(PPh₃)₄ (2.5 Mol %) is added to a solution of the above compound 72(1.7 g, 4 mmol) in toluene (25 ml) and stirred at room temperature for20 minutes. Ethylboronic acid (3.0 g, 40 mmol) is added, followed byNa₂CO₃ (8 ml, 1M, 8 mmol). The resulting mixture is heated to reflux for2 hours. After cooling to room temperature, the mixture is diluted with30% EtOAc in hexane, and then washed with H₂O and brine. The crudeproduct is purified by column chromatography (eluted with 5% EtOAc inhexane) to give compound 73 as white crystalline solid. MS 372.4 (M+1).¹H NMR (CDCl₃) δ ppm 0.97 (t, 6H), 1.04 (t, 3H), 1.30 (d, 6H), 1.71 (m,4H), 2.32 (q, 2H), 2.95 (m, 1H), 2.98 (d, 3H), 3.92 (s, 3H), 4.15 (m,1H), 4.78 (m, 1H), 6.72 (s, 1H), 6.80 (d, 1H), 7.51 (d, 1H).

Step 5. Preparation of3-Ethyl-5-(1-ethyl-propoxy)-6′-isopropyl-6-methylamino-1′H-[2,3′]bipyridinyl-2′-one

A mixture of the above compound 73 (600 mg, 1.6 mmol) in HCl (3.3 N, 3ml) is heated to 75° C. for 10 hours. After cooling to room temperature,the mixture is basified with NaOH (10N) at 0° C. The resultingprecipitate is collected by Filtration. The solid is washed with H₂O and5% EtOAc/hexane, and dried to give compound 74 as white crystallinesolid (560 mg). MS 358.3 (M+1). ¹H NMR (CDCl₃) δ ppm 0.97 (t, 6H), 1.10(t, 3H), 1.28 (d, 6H), 1.71 (m, 4H), 2.52 (q, 2H), 2.80 (m, 1H), 2.99(d, 3H), 4.13 (m, 1H), 4.80 (m, 1H), 6.16 (d, 1H), 6.73 (s, 1H), 7.51(d, 1H).

Step 6. Preparation of[2′-Ethoxy-3-ethyl-5-(1-ethyl-propoxy)-6′-isopropyl-1′,2′-dihydro-[2,3′]bipyridinyl-6-yl]-methyl-amine

K₂CO₃ (30 mg) is added a mixture of the above compound 74 (50 mg, 0.14mmol) in DMF (1 ml), followed by the addition of EtI (0.017 ml). Themixture was stirred at room temperature for 8 hours, then diluted withH₂O, and extracted with 33% EtOAc/hexane. The combined extracts arewashed with H₂O and brine, dried, and purified by column chromatography(eluted with 8% EtOAc/hexane) to give compound 75 as colorless oil. MS386.3 (M+1). ¹H NMR (CDCl₃) δ ppm 0.97 (t, 6H), 1.10 (t, 3H), 1.29 (d,6H), 1.31 (t, 3H), 1.71 (m, 4H), 2.35 (q, 2H), 2.95 (m, 1H), 2.99 (d,3H), 4.15 (m, 1H), 4.42 (q, 2H), 4.77 (m, 1H), 6.72 (s, 1H), 6.76 (d,1H), 7.50 (d, 1H).

Step 7. Preparation of Trifluoro-acetic acid3-ethyl-5-(1-ethyl-propoxy)-6′-isopropyl-6-methylamino-[2,3′]bipyridinyl-2′-ylester

Tf₂O (0.009 ml, 0.05 mmol) is added to a solution of the above compound74 (17 mg, 0.05 mmol) in CH₂Cl₂ (1 ml) at 0° C., followed by Et₃N (0.014ml, 0.1 mmol). The mixture is stirred for 30 minutes, evaporated,diluted with H₂O, and extracted with 33% EtOAc/hexane. The combinedextracts are washed with H₂O and brine, dried, and evaporated to givecompound 76 as a light yellow crystalline solid (21 mg). MS 490.4 (M+1).¹H NMR (CDCl₃) δ ppm 0.97 (t, 6H), 1.06 (t, 3H), 1.30 (d, 6H), 1.71 (m,4H), 2.35 (q, 2H), 2.98 (d, 3H), 3.06 (m, 1H), 4.17 (m, 1H), 4.87 (m,1H), 6.71 (s, 1H), 7.22 (d, 1H), 7.75 (d, 1H).

Step 8. Preparation of[3,2′-Diethyl-5-(1-ethyl-propoxy)-6′-isopropyl-[2,3′]bipyridinyl-6-yl]-methyl-amine

Pd(PPh₃)₄ (2.5 Mol %) is added to a solution of the above compound 76(15 mg, 0.03 mmol) in toluene (0.5 ml), and the mixture is stirred atroom temperature, for 20 minutes. Triethylborane (1N in hexane, 0.09 ml,0.09 mmol) is added, followed by Na₂CO₃ (0.06 ml, 1M, 0.06 mmol).Optionally, triethyl boronic acid (30 mmol) may be substituted fortriethylborane. The resulting mixture is heated to 100° C. for 4 hours.After cooling to room temperature, the mixture is diluted with 30% EtOAcin hexane, and washed with H₂O and brine. The crude is purified bycolumn chromatography (eluted with 10% EtOAc in hexane) to give compound77 as white crystalline solid. MS 370.4 (M+1). ¹H NMR (CDCl₃) δ ppm 0.99(t, 6H), 1.01 (t, 3H), 1.18 (t, 3H), 1.32 (d, 6H), 1.72 (m, 4H), 2.25(m, 2H), 2.64 (q, 2H), 2.96 (d, 3H), 3.08 (m, 1H), 4.17 (m, 1H), 4.81(m, 1H), 6.72 (s, 1H), 7.02 (d, 1H), 7.40 (d, 1H).

Example 5 Preparation of2,5-Diethyl-3-(1-ethyl-propoxy)-6-(2-methoxy-4-trifluoromethoxy-phenyl)-pyridine

Step E Preparation of 3-Chloro-5-(1-ethyl-propoxy)-pyridine

5-chloro-3-pyridinol (10 g, 0.077 mol) (78) is dissolved in anhydrousDMF (200 ml). 3-bromopentane (14.0 g, 0.093 mol) and potassium carbonate(16.0 g, 0.115 mol) are added to the solution at room temperature. Theresulting mixture is heated at 80° C. under N₂ atmosphere for 15 hours.The reaction mixture is cooled to room temperature, diluted with water(˜200 ml) and extracted with ethyl acetate (150 ml, 3 extractions). Thecombined organic layers are washed with brine (150 ml) and dried withanhydrous sodium sulfate. Purification by flash column with 5% ethylacetate in hexanes gives the product (79) as a slightly yellow liquid.

¹HNMR δ(ppm, CDCl₃) 8.17(d, J=2.4 Hz, 1H), 8.14(d, J=1.6 Hz, 1H), 7.17(t, J=2.2 Hz, 1H), 4.13(1H, m, —CHEt₂), 1.69 (m, 4H, 2X(—CH₂CH₃)), 0.95(t, J=7.2 Hz, 6H, 2X(—CH₂CH₃))

Step 2. Preparation of 3-Ethyl-5-(1-ethyl-propoxy)-pyridine

3-Chloro-5-(1-ethyl-propoxy)-pyridine (5.17 g, 0.026 mol) is dissolvedin anhydrous THF/1-methyl-2-pyrrolidinone (NMP) (100 ml/10 ml).Fe(acac)₃ (457 mg, 5% mol) is added at room temperature. C₂H₅MgBr (3.0Min ether, 10.4 ml) is added dropwise at room temperature and stirred for20 minutes. The reaction mixture was quenched with water (100 ml) andextracted with ethyl acetate (150 ml, 3 extractions), the combinedorganic layers are washed with brine(150) and dried with anhydroussodium acetate. Purification by flash column chromatography with 10%ethyl acetate in hexanes yields product 80 as a slightly yellow liquid.

¹HNMR δ(ppm, CDCl₃): 8.11(d, J=2.7 Hz, 1H), 8.04 (s, 1H), 7.01 (s, 1H),4.14(1H, m, —CHEt₂), 2.62 (q, J=7.8 Hz, —CH₂CH₃), 1.64-1.73(m, 4H,2X(—CH₂CH₃)), 1.24 (t, J=7.8 Hz, 3H —CH₂CH₃), 0.96 (t, J=7.5H, 6H,2X(—CH₂CH₃))

Step 3. Preparation of 3-Ethyl-5-(1-ethyl-propoxy)-6-chloro-pyridine

A solution of 2-(dimethylamino)ethanol (3.48 ml, 0.035 mol) in anhydroushexanes (40 ml) is treated with n-BuLi (43 ml, 1.6M in hexanes) at 0° C.and stirred at 0° C. for 30 minutes.3-Ethyl-5-(1-ethyl-propoxy)-pyridine (80) (3.35 g, 0.017 mol) is addedand stirred at 0° C. for 45 minutes. The resulting reaction mixture iscooled to −78° C. Hexachloroethane (10.26 g, 0.043 mol) is added as asolution in hexanes (60 ml). The resulting mixture is allowed to warm to0° C. over a period of 1.5 hours. The reaction is quenched with water(80 ml) and extracted with ethyl acetate (100 ml) and dichloromethane(60 ml, 2 extractions). The combined organic layers are washed withbrine (150 ml) and dried with anhydrous sodium sulfate. Purification bycolumn chromatography with hexanes/ethyl acetate ( 1/20) gives product(81) as a colorless liquid.

¹HNMR δ(ppm, CDCl₃): 7.79 (s, 1H), 7.00 (s, 1H), 4.16(1H, m, —CHEt₂),2.61(q, J=7.8 Hz, 2H —CH₂CH₃), 1.67-1.77(m, 4H, 2X(—CH₂CH₃)), 1.24 (t,J=7.8 Hz, 3H, —CH₂CH₃), 0.98(1, J=7.2 Hz, 6H, 2X(—CH₂CH₃))

Step 4. Preparation of 3,6-Diethyl-5-(1-ethyl-propoxy)-pyridine

3-Ethyl-5-(1-ethyl-propoxy)-6-chloro-pyridine (81) (2.27 g, 0.01 mol) isdissolved in anhydrous THF/1-methyl-2-pyrrolidinone (NMP) (60 ml/5.5ml). Fe(acac)₃ (177 mg, 5% mol) is added at room temperature. C₂H₅MgBr(3.0M in ether, 4.0 ml) was added dropwise at room temperature andstirred for 20 minutes. Another 2.0 ml of C₂H₅MgBr (3.0M in ether) isadded at room temperature. The reaction mixture is quenched with water(100 ml) and extracted with ethyl acetate (100 ml 3 extractions). Thecombined organic layers are washed with brine (100 ml) and dried withanhydrous sodium acetate. Purification by Hash column with 10% ethylacetate in hexanes gives product (82) as a slightly yellow liquid. ¹HNMR(δ ppm, CDCl₃): 7.92 (d, J=0.9 Hz, 1H), 6.88 (s, 1H), 4.14(1H, m,—CHEt₂), 2.80 (q, J=7.8 Hz, —CH₂CH₃), 2.60 (q, J=7.8 Hz, —CH₂CH₃),1.65-1.74(m, 4H, 2X(—CH₂CH₃)), 1.24(1, J=7.8 Hz, 6H, 2X(—CH₂CH₃)), 0.98(t, J=7.2H, 2X(—CH₂CH₃))

Step 5. Preparation of 2-Bromo-3,6-diethyl-5-(1-ethyl-propoxy)-pyridine

A solution of 2-(dimethylamino)ethanol (2.13 ml, 0.021 mol) in anhydroushexanes (20 ml) is treated with n-BuLi (26.5 ml, 1.6M in hexanes) at 0°C. and stirred at 0° C. for 40 minutes.3,6-Diethyl-5-(1-ethyl-propoxy)-pyridine (2.35 g, 0.011 mol) is addedand stirred at 0° C. for 1.5 hours. The resulting reaction mixture iscooled to −78° C. Carbon tetrabromide (8.80 g, 0.027 mol) is added as asolution in hexanes (50 ml). The resulting mixture is stirred at −78° C.for 1 hour and 0° C. for 1 hour. The reaction is quenched with water (80ml) and extracted with ethyl acetate (100 ml) and dichloromethane (60ml, 2 extractions). The combined organic layers are washed with brine(150 mlX1) and dried with anhydrous sodium sulfate. Purification bycolumn chromatography with hexanes/ethyl acetate ( 1/20) gave product(83) as a brown liquid. ¹HNMR (δ ppm, CDCl₃) 6.91 (s, 1H), 4.10(1H, m,—CHEt₂), 2.76 (q, J=7.6 Hz, —CH₂CH₃), 2.66 (q, J=7.6 Hz, —CH₂CH₃),1.64-1.71(m, 4H, 2X(—CH₂CH₃)), 1.15-1.26(m, 2X(—CH₂CH₃)), 0.92-1.01 (m,2X(—CH₂CH₃)

Step 6. Preparation of2,5-Diethyl-3-(1-ethyl-propoxy)-6-(2-methoxy-4-trifluoromethoxy-phenyl)-pyridine

2-Bromo-3,6-diethyl-5-(1-ethyl-propoxy)-pyridine (83) (90 mg, 0.3 mmol)is dissolved in toluene (3 ml) followed by the addition ofTetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄)(34 mg),4-trifluoromethoxy-2-methoxy-phenylboronic acid (120 mg, 0.5 mmol) andaqueous sodium carbonate (0.6 ml, 1.0M in water). The resulting mixtureis heated at 90° C. for 15 hours. The reaction mixture is cooled to roomtemperature and diluted with water (20 ml), extracted with ethyl acetate(15 ml, 3 extractions). The combined organic layers are washed withbrine and dried with anhydrous sodium sulfate. Purification by columnchromatography, eluting with 4% ethyl acetate in hexanes provides theproduct (84). ¹HNMR δ (ppm, CDCl₃) 7.25(d, J=8.4 Hz, 1H, phenyl-H), 6.97(s, 1H, pyridyl-H), 6.89 (d, J=7.6 Hz, 1H, phenyl-H), 6.78 (s, 1H,phenyl-H), 4.19 (1H, m, —CHEt₂), 3.76 (s, 3H, —OCH₃), 2.85 (br,—CH₂CH₃), 2.39 (br, —CH₂CH₃), 1.72-1.78(m, 4H, 2X(—CH₂CH₃) on pentylgroup), 1.23 (t, J=7.2 Hz, 3H, —CH₂CH₃), 1.07(t, J=7.2 Hz, 3H, —CH₂CH₃),1.00(1, J=7.2 Hz, 6H, 2X(—CH₂CH₃) on pentyl group) LC-MC data [M+1]⁺412.25, RT 2.75 min.

Example 6 Preparation ofDiethyl-[2-ethyl-6-(2-methoxy-4-Trifluoromethoxy-Phenyl)-5-methyl-pyridin-3-yl]-amineStep 1. Preparation of2-Ethyl-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine(85)

Tetrakistriphenylphosphinepalladium(0) (0.03 g, 0.03 mmol) is added to2-chloro-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine(0.10 g, 0.27 mmol) in toluene (5 mL). Ethyl boronic acid (0.1 g, 1.1mmol) and potassium carbonate (0.07 g, 0.55 mmol)) are added to thissolution, and the reaction is heated to reflux for 17 hours. The productis extracted with ethyl acetate (20 mL). Combined extracts are washedwith brine (20 mL), dried over sodium sulfate, and concentrated invacuo. Purification by flash column chromatography (5% EtOAC-hexane)yields2-ethyl-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridineas a yellow solid TLC R_(f) 0.55 (elution with 10% ethyl acetate-hexane)

Step 2. Preparation of2-Ethyl-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl-amine(86)

10% Pd/C (0.1 g) is added to a solution of2-ethyl-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine(0.3 g, 0.84 mmol) in ethanol (10 mL). The mixture is hydrogenated at apressure of 50 psi for 4 hours. The mixture is filtered through celiteand evaporated to dryness under reduced pressure to give2-ethyl-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-ylamineas a yellow solid which is used without further purification TLC R_(f)0.30 (elution with 5% methanol-methylene chloride).

Step 3. Preparation of2-Ethyl-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-3-nitro-pyridine(87)

A solution of 2-ethyl-6-(2-methoxy4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl amine (0.07 g, 0.21mmol), 3-pentanone (0.02 mL, 0.21 mmol) and acetic acid (0.0.1 mL, 0.21mmol) in dry dichloroethane (3 mL) is treated with sodiumtriacetoxyborohydride (0.06 g, 0.30 mmol) and stirred at roomtemperature overnight. The resulting mixture is diluted with CH₂Cl₂ (20mL) and washed with saturated aqueous NaCl (50 mL). The organic portionis dried over Na₂SO₄, filtered and concentrated under reduced pressure.Purification by preparative TLC (5% methanol-CH₂Cl₂) givesDiethyl-[2-ethyl-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-amine(87) as a yellow solid TLC R_(f) 0.45 (elution with 5%methanol-methylene chloride)

Example 6A Preparation of2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-5-methyl-N,N-dipropylpyridin-3-amine(88)

2-ethyl-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-5-methyl-N,N-dipropylpyridin-3-amine(88) is prepared by a method analogous to that given in Example 6. TLCR_(f) 0.4 (elution with 5% methanol-methylene chloride).

Example 6B Preparation of2-Ethyl-6-[2-methoxy-4-trifluoromethoxy-phenyl)-5-methylpyridin-3-yl]-propyl-amine(89)

2-Ethyl-6-[2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-propyl-anine(89) is prepared in a manner similar to that given in example 6. TLCR_(f) 0.35 (elution with 5% methanol-methylene chloride)

Example 7 Preparation of[2-methoxy-6-(2-Methoxy-4-Trifluoromethoxy-phenyl)5-methyl-pyridin-3-yl]-dipropyl-amineand[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-propyl-amine

Step 1. Preparation ofN[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-propionamide(91)

Propionyl chloride (0.058 ml, 0.67 mmol) is added to a solution of2-methoxy-6-(2methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-ylamine(0.2 g, 0.61 mmol) and diisopropylethylamine (0.13 ml, 0.73 mmol) inCH₂Cl₂ (1.5 ml) at room temperature. The mixture is kept at roomtemperature for 3 hours, and is then diluted with EtOAc. The mixture iswashed with 1N NaOH and brine. After drying over Na₂SO₄, the solvent isremoved under reduced pressure and the residue is purified by flashcolumn chromatography (hexane/EtOAc= 4:1) to give theN-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-propionamide.Rf (hexane/EtOAc= 4:1)= 0.2.

Step 2. Preparation ofN-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-N-propyl-propionamide(92)

60% NaH (23 mg, 0.58 mmol) is added to a solution ofN-[2-methoxy-6-(2-methoxy-4-trifluoromethoxyphenyl)-5-methyl-pyridin-3-yl]-propionamide(0.15 g, 0.39 mmol) in DMF (1 ml) at room temperature. After stirring atroom temperature for 20 minutes, iodo propane (0.058 ml, 0.58 mmol) isadded. The mixture is stirred at room temperature for 3 days. 20 ml ofwater is added and the mixture is extracted with EtOAc. The combinedextracts are washed with brine and dried over Na₂SO₄. The solvent isremoved under reduced pressure and the residue is purified by flashcolumn chromatography to giveN-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-N-propyl-propionamide.Rf (hexane/EtOAc= 2:1)=0.42.

Step 3. Preparation of[2-Methoxy-6(2-methoxy-4-trifluoromethoxy-phenyl)->5-methyl-pyridin-3-yl]-dipropyl-amine (93) and[2-Methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-propyl-amine(94)

A 1M solution of LiAlH₄ in THF (0.52 ml, 0.52 mmol) at 0° C. is added toa solution ofN-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-N-propyl-propionamide(94) (0.11 g, 0.26 mmol) in THF (1 ml). The mixture is stirred at 0° C.for 30 minutes and at room temperature for 15 hours. The reaction isquenched by ether containing water (5 ml) at 0° C. Water (1 ml) andEtOAc (20 ml) are added to the mixture and the suspension is stirred atroom temperature for 20 minutes. MgSO₄ (2 g) and Celite (2 g) are addedand the mixture is stirred at room temperature for 40 minutes. Theinorganic salts are removed and washed with EtOAc. The combinedfiltrates are concentrated under reduced pressure and the residue ispurified by flash column chromatography to give[2-Methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-dipropyl-amine(93); Rf (hexane/EtOAc= 9:1)= 0.39, MS m/z 413.4 (M+H) and[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-propyl-amine;Rf (hexane/EtOAc=9:1) 0.35, MS m/z 371.3 (M+H)(94)

Example 8 Additional 3-Alkoxy Compounds of Formula I

The following compounds were prepared using the methods shown in aboveSchemes I and II and further illustrated by Examples 1 and 2. TABLE I

Analytical Data Cpd. MS (M + 1) or NMR # R_(X) R₁ R₃ R₄ Ar Name (ppm)100 1-ethyl-propyl H H methyl 2,4-dichloro-phenyl2-(2,4-Dichloro-phenyl)-5-(1- 0.98(t, 6H), 1.75(m, 4H),ethyl-propoxy)-3-methyl- 2.15(s, 3H), 4.20(m, 1H), 7.05 pyridine (s,1H), 7.22(6, 1H), 7.35(d, 1H), 7.43(s, 1H), 8.20(s, 1H) 1011-ethyl-propyl Cl H methyl 2,4-dichloro-phenyl2-(2,4-Dichloro-phenyl)-5-(1- 1.02(1, 6H), 1.78(m, 4H),ethyl-propoxy)-3-methyl-6- 2.15(s, 3H), 4.22(m, 1H), 7.05chloro-pyridine (s, 1H), 7.22(d, 1H), 7.30(d, 1H), 7.44(s, 1H) 1021-ethyl-propyl H Cl methyl 2,4-dichloro-phenyl2-(2,4-Dichloro-phenyl)-5-(1- 1.02(t, 6H), 1.80(m, 4H),ethyl-propox)-3-methyl-4- 2.18(s, 3H), 4.30(m, 1H) 7.22 chloro-pyridine(d, 1H), 7.34(d, 1H), 7.48(s, 1H), 8.20(s, 1H). 103 1-ethyl-propyl H Hmethyl 2-melhoxy-4- 2-(2-methoxy-4- 370.2(M + 1) trifluoromethoxy-trifluoromethoxy-phenyl)-5- phenyl (1-ethyl-propoxy)-3-methyl- pyridine104 1-ethyl-propyl Cl H methyl 2-methoxy-4- 2-(2-methoxy-4- 1.02(t, 6H),1.78(m, 4H), trifluoromethoxy- trifluoromethoxy-phenyl)-5- 2.16(s, 3H),3.78(s, 3H), 4.20 phenyl (1-ehtyl-propoxy)-3-methyl- (m, 1H), 6.78((s,1H), 6.90(d, chloro-pyridine 1H), 7.02(s, 1H), 7.22(d, 1H). 1051-ethyl-propyl methoxy H methyl 2-(2-methoxy-4- 400.39(M + 1)trifluorornethoxy- trifluoromethoxy-phenyl)-5- phenyl(1-ethyl-propoxy)-3- methoxy-6-methyl-pyridine 106 1-ethyl-propyl ethylH methyl 2-methoxy-4- 2-(2-methoxy-4- 10.98(t, 6H), 1.22(t, 3H), 1.75trifluoromethoxy- trifluoromethoxy-phenyl)-5- (m, 1H), 2.06(s, 3H),2.82(q, phenyl (1-ethyl-propoxy)-3-methyl- 2H), 3.78(s, 3H), 4.186-ethyl-pyridine (m, 1H), 6.73(d, 1H), 6.90 (dd, 1H), 6.92(s, 1H),7.22(d, 1H) 107 1-ethyl-propyl CH₃NH H methyl 4-isopropyl-6-[3-Methyl-5-(1-ethyl- methoxy-2-pyridyl propoxy)-5′-isopropyl-3′-methoxy-[2,2′]bipyridinyl-6- yl]-methyl-amine 108 1-ethyl-propyl CH₃NH Hethyl 4-isopropyl-6- [3-Ethyl-5-(1-ethyl- methoxy-2-pyridylpropoxy)-5′-isopropyl-3′- methoxy-[2,2′]bipyridinyl-6- yl]-methyl-amine109 1-ethyl-propyl CH₃O H methyl 4-isopropyl-6- methoxy-2-pyridylpropoxyl]-5-isopropyl-6,3′- dimethoxy-[2.2′]bipyridinyl 1101-ethyl-propyl CH₃O H ethyl 4-isopropyl-6- methoxy-2-pyridyl5′-isopropyl-6,3′-dimethoxy- [2.2′]bipyridinyl 111 1-ethyl-propyl CH₃NHH methyl 2-ethyl-4-isopropyl-5- [2′-Ethyl-5-(1-ethyl methoxy-3-pyridylpropoxy)-6′-isopropyl-5′- methoxy-3-methyl- [2,3′]bipyridinyl-6-yl]-methyl-amine 112 1-ethyl-propyl CH₃NH H ethyl 2-ethyl-4-isopropyl-5-[3,2′-Diethyl-5-(1-ethyl- methoxy-3-pyridyl propoxy]-6′-isopropyl-5′-methoxy-[2,3]bipyridinyl-6- yl]-methyl-amine 113 1-ethyl-propyl ethyl Hmethyl 2-ethyl-4-isopropyl-5- 6,2′-Diethyl-5-(1-ethyl- methoxy-3-pyridylpropoxy)-6′-isopropyl-5′- methoxy-3-methyl [2,3′]bipyridinyl 1141-ethyl-propyl ethyl H ethyl 2-ethyl-4-isopropyl-5-3,6,2′-Triethyl-5-(1-ethyl- methoxy-3-pyridyl propoxy)-6′-isopropyl-5′-methoxy-[2,3′]bipyridinyl 115 1-ethyl-propyl CH₃NH H methyl 2-methyl-4-5-(1-Ethyl-propoxy)-N6′- isopropylamino-5- isopropyl-5′-methoxy-methoxy-3-pyridyl 3,2′,N6-trimethyl- [2,3′]bipyridinyl-6,6′-diamine 1161-ethyl-propyl CH₃NH H ethyl 2-methyl-4- 3-Ethyl-5-(1-ethyl-propoxy)-isopropylamino-5- N6′-isopropyl-5′-methoxy methoxy-3-pyridyl2′,N6-dimethyl- 2,3′]bipyridinyl-6,6′-diamine 117 1-ethyl-propyl ethyl Hmethyl 2-methyl-4- [6-Ethy[-5-(1-ethyl-propoxy)- isopropylamino-5-5′-methoxy-3,2′-dimethyl- methoxy-3-pyridyl [2,3′]bipyridinyl-6′-yl]-isopropyl-amine 118 1-ethyl-propyl ethyl H ethyl 2-methyl-4-[3,6-Diethyl-5-(1-ethyl- isopropylamino-5- propoxy)-5′-methoxy-2′-methoxy-3-pyridyl methyl[2,3′]bipyridinyl-6′- yl]-isopropyl-amine 1191-ethyl-propyl CH₃NH H methyl 2,4-6-trimethyl-5-(4-[3-Methyl-5-(1-ethyl- methyl-oxazol-2-yl) propoxy)-2′,4,6′-trimethyl-5′-(4-methyl-oxazol-2-yl)- 2,3′]bipyridinyl-6-yl]- methyl-amine 1201-ethyl-propyl CH₃NH H ethyl 2,4-6-trimethyl-5-(4- [3-Ethyl-5-(1-ethyl-methyl-oxazol-2-yl) propoxy)-2′,4,6′-trimethyl-5′-(4-methyl-oxazol-2-yl)- 2,3′]bipyridinyl-6-yl]- methyl-amine 1211-ethyl-propyl Ethyl H methyl 2,4,6-trimethyl-5-(4-3-Methyl-6-ethyl-5-(1-ethyl- methyl-oxazol-2-yl)propoxyl)-2′,4′,6′-trimethyl-5′- (4-methyl-oxazol-2-yl)-[2,3′]bipyridinyl 122 1-ethyl-propyl Ethyl H ethyl 2,4,6-trimethyl-5-(4-3,6-Diethyl-5-(1-ethyl- methyl-oxazol-2-yl)propoxy)-2′,4′,6′,-trimethyl-5′- (4-methyl-oxazol-2-yl)-[2,3′]bipyridinyl 123 1-ethyl-propyl CH₃NH H methyl 4-isopropoxy-6-[3-Methyl-5-(1-ethyl- methoxy-3-pyridyl propoxy)-6′-isopropoxy-4′-methoxy-[2,3′]bipyridinyl-6- yl]-methyl-amine 124 1-ethyl-propyl CH₃NH Hmethyl 4-isopropoxy-6- [3-Ethyl-5-(1-ethyl- methoxy-3-pyridylpropoxy)-6′-isopropoxy-4′- methoxy-[2,3′]bipyridinyl-6- yl]-methyl-amine125 1-ethyl-propyl Ethyl H methyl 4-isopropoxy-6-3-Methyl-6-ethy]-5-(1-ethyl- methoxy-3-pyridyl propoxy)-6-isopropoxy-4′-methoxy[2,3′]bipyridinyl 126 1-ethyl-propyl Ethyl H ethyl4-isopropoxy-6- 3,6-Diethyl-5-(1-ethyl- methoxy-3-pyridylpropoxy)-6-isopropoxy-4- methoxy-[2,3′]bipyridinyl

The compounds shown in Table II were prepared using the methods shown inabove Schemes I, II, IV and V and further illustrated by Examples 1, 2,4, and 5. TABLE II

Cmp Analytical Data # R₁ R₃ R₄ R₅ R₆ A IUPAC Name MS(M + 1) 127 CH₃NH HCH₃ CH₃O CF₂O CH 3-(1-ethylpropoxy)-6-[2-methoxy-4- 399.4(trifluoromethoxy)phenyl]-N,5- dimethylpyridin-2-amine 128 CH₃NH HCH₃CH₂ CH₃O CF₂O CH 5-ethyl-3-(1-ethylpropoxy)-6-[2- 413.4methoxy-4-(trifluoromethoxy)phenyl- N-methylpyridin-2-amine 129 CH₃NH HBr CH₃O CF₂O CH 5-bromo-3-(1-ethylpropoxy)-6-[2- 463.3, 465.3methoxy-4-(trifluoromethoxy)phenyl]- N-methylpyridin-2-amine 130 CH₃NH HCH₃CH₂ Cl CH₃O CH 6-(2-chloro-4-methoxypkenyl)-5-ethyl- 363.3, 365.33-(1-ethylpropoxy)-N-methylpridin-2- amine 131 CH₃NH H CH₃ Cl CH₃O CH6-(2-chloro-4-methoxyphenyl)-3-(1- 349.4, 351.4ethylpropoxy)-N,5-dimethylpyridin-2- amine 132 CH₃NH H Br CH₃O (CH₃)₂CHOCH 5-bromo-3-(1-ethylpmopoxy)-6-(4- 437.3, 439.3isopropoxy-2-methoxyphenyl)-N- methylpyridin-2-amine 133 CH₃NH H CH₃ Cl(CH₃)₂CHO CH 6-(2-chloro-4-isopropoxyphenyl)-3-(1- 377.4, 379.4ethylpropoxy)-N,5-dimethylpyridin-2- amine 134 CH₃NH H Br Cl (CH₃)₂CHOCH 5-bromo-6-(2-chloro-4- 441.2, 443.2isopropoxyphenyl)-3-(1-ethylpropoxy)- 445.2 N-methylpyridin-2-amine 135CH₃NH H Cl CH₃O CHF₂O CH 5-chloro-6-[4-(difluoromethoxy)-2- 401.4, 403.4methoxyphenyl]-3-(1-ethylpropoxy)-N- methylpyridin-2-amine 136 CH₃NH HBr CH₃O CHF₂O CH 5-bmomo-6-[4-(difluomomethoxy)-2- 445.2, 447.2methoxyphenyl]-3-(1-ethylpropoxy)-N- methylpyridin-2-amine 137 CH₃NH HCH₃ CH₃O (CH₃)₂CHO CH 3-(1-ethylpropoxy)-6-(4-isopropaxy-2- 373.4methoxyphenyl)-N,5-dimethylpyridin-2- amine 138 CH₃NH H CH₃CH₂ CH₃OCHF₂O CH 6-[4-(difluoromethoxy)-2- 395.5 methoxyphenyl]-5-ethyl-3-(1-ethylpropoxy)-N-methylpyridin-2-amine 139 CH₃NH H CH₃ CH₃O (CH₃)₂CH CH3-(1-ethylpropoxy)-6-(4-isopropyl-2- 357.5methoxyphenyl)-N,5-dimethylpyridin-2- amine 140 CH₃NH H Br CH₃O (CH₃)₂CHCH 5-ethyl-3-(1-ethylpropoxy)-6-(4- 371.4 isopropyl-2-methoxyphenyl)-N-methylpyridin-2-amine 141 CH₃NH H Br CH₃O (CH₃)₂CH CH5-bromo-3-(1-ethylpropoxy)-6-(4- 421.4, 423.4isopropyl-2-methoxyphenyl)-N- methylpyridin-2-amine 142 CH₃NH H Br ClCH₃O CH 5-bromo-6-(2-chloro-4-methoxy 413.2, 415.2,phenyl)-3-(1-ethylpropoxy)-N- 417.2 methylpyridin-2-amine 143 CH₃NH H HCl CH₃O CH 6-(2-chloro-4-methoxyphenyl)-3-(1- 335.2, 337.2ethylpropoxy)-N-methylpyridin-2-amine 144 CH₃NH H Br CF₃O CH₃O CH5-bromo-3-(1-ethylpropoxy)-6-[4- 463.1, 465.1methoxy-2-(trifluoromethoxy)phenyl]- N-methylpyridin-2-amine 145 CH₃NH HH CF₃O CH₃O CH 3-(1-ethylpropoxy)-6-[4-methoxy-2- 385.2(trifluoromethoxy)phenyl]-N- methylpyridin-2-amine 146 CH₃NH H CH₃CH₂CF₃O CH₃O CH 5-ethyl-3-(1-ethylpropoxy)-6-[4- 413.3methoxy-2-(trifluoromethoxy)phenyl]- N-methylpyridin-2-amine 147 CH₃NH HCH₃ CF₃O CH₃O CH 3-(1-ethylpropoxy)-6-[4-methoxy-2- 399.3(trifluoromethoxy)phenyl]-N,5- dimethy-pyridin-2-amine 148 CH₃NH H CH₃CH₃O CF₃ CH 3-(1-ethylpropoxy)-6-[2-methoxy-4- 383.3(trifluoromethyl)phenyl]-N,5- dimethylpyridin-2-amine 149 H H CH₃ CH₃OCF₃ CH 4-chloro-5-(1-ethylpropoxy)-2-[2- 388.2, 390.2methoxy-4-(trifluoromethyl)phenyl]-3- methylpyridine 150 Cl H CH₃ CH₃OCF₃ CH 2-chloro-3-(1-ethylpyopoxy)-6-[2- 333.2, 390.2methoxy-4-(trifiuoromethyl)phenyl]-5- methylpyridine 151 H H CH₃ CH₃OCF₃ CH 5-(1-ethylpropoxy)-2-[2-methoxy-4- 354.2(trifluoromethyl)pheuyl]-3- methylpyridine 152 CH₃CH₂ H CH₃CH₂ CF₃O CH₃OCH ′2,5-diethyl-3-(1-ethylpropoxy)-6-[4- 412.25 methoxy-2-(trifluoromethoxyl)phenyl]pyridine 153 CH₃CH₂ H CH₃CH₂ CH₃O (CH₃)₂CHO CH2,5-diethyl-3-(1-ethylpropoxy)-6-(4- 386.30isopropoxy-2-methoxyphenyl)pyridine 154 CH₃CH₂ H CH₃CH₂ CH₃O CH₃CH₂O CH2-(4-ethoxy-2-methoxyphenyl)-3,6- 372.27diethyl-5-(1-ethylpropoxy)pyridine 155 CH₃CH₂ H CH₃CH₂ CH₃O (CH₃)₂CHO CH2,5-diethyl-3-(1-ethylpropoxy)-6-(4- 370.33isopropyl-2-methoxyphenyl)pyridine 156 CH₃CH₂ H CH₃CH₂ CH₃O CHF₂O CH2-(4-(difluoromethoxy)-2- 394.25 methoxyphenyl]-3,6-diethyl-5-(1-ethylpropoxy)pyridine 157 CH₃CH₂ H CH₃CH₂ CH₃O CF₃O CH2,5-diethyl-3-(1-ethylpropoxy)-6-[2- 412.25 methoxy-4-(trifluoromethoxy)phenyl]pyridine 158 CH₃CH₂ H CH₃CH₂ CH₃CH₂ (CH₃)₂CHNH N2′,3,6-methyl-5-(1-ethylpropoxy)-N- 334.27isopropyl-2,3′-bipyridin-6′-amine 159 CH₃NH H CH₃ CH₃O (CH₃)₂CH N5-(1-ethylpropoxy)-6′-isopropyl-2′- 358.4methoxy-N,3-dimethy-2,3′-bipyridin-6- amine 160 CH₃NH H CH₃CH₂ CH₃O(CH₃)₂CH N 3-ethyl-5-(1-ethylpropoxy)-6′-isopropyl- 372.52′-methoxy-N-methyl-2,3′-bipyridin-6- amine 161 CH₃CH₂ H CH₃CH₂ CH₃O(CH₃)₂CH N 3,6-diethyl-5-(1-ethylpropoxy)-6′- 371.33isopropyl-2′-methoxy-2,3′-bipyridine 162 CH₃NH H Br CH₃O (CH₃)₂CH N3-bromo-5-(1-ethylpropoxy)-6′- 422.3, 424.3isopropyl-2′-methoxy-N-methyl-2,3′- bipyridine-6-amine 163 CH₃NH H HCH₃O (CH₃)₂CH N 5-(1-ethylpropoxy)-6′-isopropyl-2′- 344.3methoxy-N-methyl-2,3′-bipyridin-6- amine 164 CH₃NH H CH₃CH₂ CH₃CH₂O(CH₃)₂CH N 2′-ethoxy-3-ethyl-5-(1-ethylpropoxy)-6′- 386.3isopropyl-N-methyl-2,3′-bipyridin-6- amine 165 (CH₃CH₂) H CH₃CH₂ CH₃O(CH₃)₂CH N 2′-ethoxy-N,3-diethyl-5-(1- 414.4 (CH₃)N-ethylpropoxy)-6′-isopropyl-N-methyl- 2,3′-bipyridin-6-amine 166 CH₃NH HCl CH₃O (CH₃)₂CH N 3-chloro-5-(1-ethylpropoxy)-6′- 378.3, 330.3isopropyl-2′-methoxy-N-methyl-2,3′- bipyridin-6-amine 167 CH₃NH H CH₃CH₂CH₃CH₂ (CH₃)₂CH N 2′,3-diethyl-5-(1-ethylpropoxy)-6′- 370.4isopropyl-N-methyl-2,3′-bipyridin-6- amine 168 CH₃NH H CH₃CH₂ CH₃CH₂O(CH₃)₂CH N [2′-Ethoxy-3-ethyl-5-(1-ethyl-propoxy)-6′-isopropyl-[2,3′]bipyridinyl-6-yl]- methyl-amine 169 CH₃NH H CH₃CH₂CH₃ (CH₃)₂CH N [2′-Methyl-3-ethyl-5-(1-ethyl-propoxy)-6′-isopropyl-[2,3′]bipyridinyl-6-yl]- methyl-amine 170 CH₃NH H CH₃CH₂CH₃ (CH₃)₂CH—O N [2′-Methyl-3-ethyl-5-(1-ethyl-propoxy)-6′-isopropoxy-[2,3′]bipyridinyl-6-yl]- methyl-amine 171 CH₃NH H CH₃CH₂CH₃ (CH₃)₂N N 3-Ethyl-5-(1-ethyl-propoxy)-2′,N6,N6′,N6′-tetramethyl-[2,3]bipyridinyl-6,6′- diamine 172 CH₃NH H CH₃ HOCH₂(CH₃)₂CH N [2′-Hydroxymethyl-3-methyl-5-(1-ethyl-propoxy)-6′-isopropyl-[2,3′]bipyridinyl- 6-yl]-methyl-amine 173 CH₃NH HCH₃CH₂ HOCH₂ (CH₃)₂CH N [2′-Hydroxymethyl-3-ethyl-5-(1-ethyl-propoxy)-6′-isopropyl-[2,3′]bipyridinyl- 6-yl]-methyl-amine 174 CH₃O HCH₃CH₂ HOCH₂ (CH₃)₂CH N [5-(1-Ethyl-propoxy)-6′-isopropyl-6-methoxy-3-methyl-[2,3′]bipyridinyl-2′- yl]-methanol 175 CH₃O H CH₃CH₂HOCH₂ (CH₃)₂CH N [5-(1-Ethyl-propoxy)-6′-isopropyl-6-methoxy-3-ethyl-[2,3′]bipyridinyl-2′- yl]-methanol 176 CH₃NH H CN CH₃O(CH₃)₂CH—O CH 5-(1-Ethyl-propoxy)-2-(4-isopropoxy-2-methoxy-phenyl)-6-methylamino- nicotinonitrile 177 NH₂CH₂ H CH₃CH₂ CH₃O(CH₃)₂CH—O CH C-[5-Ethyl-3-(1-ethy-propoxy)-6-(4-isopropoxy-2-methoxy-phenyl)-pyridin- 2-yl]-methylamine 178 CH₃NH HCH₃CH₂ CH₃CH₂ (CH₃)₂CH N [3,2′-Diethyl-5-(1-ethyl-propoxy)-6′-isopropyl-[2,3′]bipyridinyl-6-yl]- methyl-amine 179 CH₃CH₂ H CH₃CH₂ CH₃OCF₃ N 3,6-Diethyl-5-(1-ethyl-propoxy)-2′- methoxy-6′-trifluoromethyl-[2,3′]bipyridinyl 180 CH₃NH H CH₃CH₂ CH₃ (CH₃)₂CH N[3ethyl-2′-methyl-5-(1-ethyl-propoxy)-6′-isopropyl-[2,3′]bipyridinyl-6-yl]- methyl-amine 181 CH₃NH H CH₃CH₂(CH₃)₂ (CH₃)₂CH N [3-Ethyl-5-(1-ethyl-propoxy)-2′- CH—Oisopropoxy-6′-isopropyl- [2,3′]biyridinyl-6-yl]-methyl-amine 182 CH₃CH₂H CH₃CH₂ Cl CH₃O CH 2-(2-Chloro-4-methoxy-phenyl)-3,6-diethyl-5-(1-ethyl-propoxy)-pyridine 183 CH₃CH₂ H CH₃CH₂ Cl CH₃CH₂O CH2-(2-Chloro-4-ethoxy-phenyl)-3,6- diethyl-5-(1-ethyl-propoxy)-pyridine184 CH₃NH H CH₃ CH₃CH₂O (CH₃)₂CH N [2′-Ethoxy-5-(1-ethyl-propoxy)-6′-isopropyl-3-methyl-[2,3′]bipyridinyl-6- yl]-methyl-amine 185 CH₃NH H CH₃CH₃CH₂ (CH₃)₂CH N [2′-Ethyl-5-(1-ethyl-propoxy)-6-isopropyl-3-methyl-[2,3′]bipyridinyl-6- yl]-methyl-amine 186 CH₃NH HCH₃CH₂ Cl (CH₃)₂CH CH 2-(2-Chloro-4-isopropoxy-phenyl)-3,6-diethyl-5-(1-ethyl-propoxy)-pyridineOther alkoxy pyridinyl compounds Formula I:

-   187.    (2,4-dichlorophenyl)-5-(1-ethyl-propoxy)-3-methyl-pyridin-2-yl-1-N-oxide    MS (M+1):340.1, 344.1-   188.    (2-methoxy,4-trifluoromethylphenyl-5-(1-ethyl-propoxy)-3-methyl-pyridine-2-yl-1-N-oxide    MS (M+1) 340.1, 342.1, 344.1-   189.    5-(1-ethylpropoxy)-2-[2-methoxy-4-(trifluoromethyl)phenyl]-3-methylpyridine    1-oxide MS 370.4-   190.    3-Ethyl-5-(1-ethyl-propoxy)-6,6′-diisopropyl-4′-methoxy-[2,3′]bipyridinyl

Example 9 Additional 3-Amino Compounds Formula I

The following compounds were prepared using the methods shown in aboveScheme III and further illustrated by Example 3, 6 and 7. TABLE III

Analytical Data Cpd. MS (M + 1) or NMR # R_(X) R_(Y) R₃ Ar Name (ppm)191 propyl propyl chloro 2-methoxy-4-6- [5-Ethyl-6-(2-methoxy-4,6-389.3, 391.3 dimethyl-phenyl dimethyl-phenyl)-2-methyl-4-chloro-pyridin-3-yl]-dipropyl- amine 192 propyl cyclopropyl H2-methyl-4-methoxy- Cyclopropylmethyl-[5-ethyl-6- MS 353(M + H). NMR7.30(s, 1H), methyl phenyl (2-methyl-4-methoxy-phenyl)- 7.11(d, 1H),6.80(s,1H), 6.76(d, 1H), 2-methyl-pyridin-3-yl]-propyl- 3.83(s, 3H),3.11(t, 2H), 2.83(d, 2H) amine 2.57(s, 3H), 2.37(q, 2H), 2.04(s, 3H),1.48(m, 2H), 1.01(t, 3H), 0.90(t, 3H), 0.89(m, 1H), 0.42(m, 2H), 0.01(m,2H). 193 propyl isopropyl H 2-methyl-4-methoxy-Isopropylmethyl-[5-ethyl-6-(2- MS 355(M + H), NMR 7.26(d, 1H) phenylmethyl-4-methoxy-phenyl)-2- 7.11(d, 1H), 6.80(s, 1H), 6.78(d, 1H),methyl-pyridin-3-yl]-propyl- 3.83(s, 3H), 2.90(t, 2H), 2.80(d, 2H),amine 2.57(s, 3H), 2.37(q, 2H), 2.08(s, 3H), 1.73(m, 1H), 1.49(m, 2H),1.02(t, 3H), 0.94(d, 6H), 0.89(t, 3H). 194 propyl 3-methyl- H2-methyl-4-methoxy- 3-Methyl-butyl-[5-ethyl-6-(2- MS 359(M + H), NMR7.24(s, 1H) butyl phenyl methyl-4-methoxy-phenyl)-2- 7.12(d, 1H),6.80(s, 1H), 6.78(d, 1H), methyl-pyridin-3-yl]-propyl- 3.83(s, 3H),3.00(q, 2H), 2.93(q, 2H), amine 2.52(s, 3H), 2.37(q, 2H), 2.07(s, 3H),1.59(m, 1H), 1.50(m, 2H), 1.37(m, 2H), 1.02(d, 6H), 0.90(m, 9H). 195propyl benzyl H 2-methyl-4-methoxy- Benzyl-[5-ethyl-6-(2- 389.2 phenylmethyl-4-methoxy-phenyl)-2- methyl-pyridin-3-yl]-propyl- amine 196propyl pyridin-2-yl H 2-methyl-4-methoxy- Pyridin-2-ylmethyl-[5-ethyl-6-390.3 methyl phenyl (2-methyl-4-methoxy-phenyl)-2-methyl-pyridin-3-yl]-propyl- amine 197 propyl ethyl H2-methyl-4-methoxy- [5-ethyl-6-(2- MS 327(M + H) NMR 7.25(s, 1H), phenylmethyl-4-methoxy-phenyl)-2- 7.11(d, 1H), 5.80(s, 3H), 6.75(d, 2H),methyl-pyridin-3-yl]-ethyl- 3.81(s, 3H), 3.05(q, 2H), 2.96(t, 2H),propyl-amine 2.52(s, 3H), 2.05(q, 2H), 2.05(s, 3H), 2.48(m, 2H), 1.01(t,3H), 1.00(t, 3H), 0.89(t, 3H). 198 propyl propyl H 2,4-dimethoxyphenyl[5-Ethyl-6-(2,4-dimethoxy- MS 357(M + H) NMR 7.24(s, 1H),phenyl)-2-methyl-pyridin-3- 7.15(d, 1H), 6.55(d, 1H), 6.51(s, 1H)yl]-dipropyl-amine 3.84(s, 3H), 3.72(s, 3H), 2.92(t, 4H), 2.51(s, 3H),2.40(q, 2H), 1.48(m, 4H), 1.06(t, 3H), 0.88(t, 6H) 199 propylcyclopropyl H 2,4-dimethoxyphenyl Cyclopropylmethyl-[5-Ethyl- MS 369(M +H) NMR 7.28(s, 1H), methyl 6-(2,4-dimethyoxy-phenyl)-2- 7.16(d, 1H),6.56(d, 1H), 6.50(s, 1H) methyl-pyridin-2-yl]-propyl 3.84(s, 3H),3.72(s, 3H), 3.09(t, 2H), amine 2.83(d, 3H), 2.54(s, 3H), 2.39(q, 2H),1.48(m, 2H), 1.05(t, 3H), 0.89(t, 3H), 0.88(m, 1H), 0.44(m, 2H), 0.06(m,2H) 200 propyl 3-methyl H 2,4-dimethoxyphenyl 3-Methyl-butyl-[5-Ethyl-MS 385(M + H) NMR 7.22(s, 1H), butyl 6-(2,4-dimethyoxy-phenyl)-2-7.18(d, 1H), 6.56(d, 1H), 6.50(s, 1H) methyl-pyridin-2-yl]-propyl3.87(s, 3H), 3.72(s, 3H), 2.98(t, 2H), amine 2.91(t, 2H), 2.52(s, 3H),2.41(q, 2H), 1.59(m, 2H), 1.49(m, 2H), 1.38(m, 2H), 1.06(t, 3H), 0.90(d,6H), 0.88(t, 3H) 201 propyl benzyl H 2,4-dimethoxyphenylBenzyl-[5-Ethyl- 405.4 6-(2,4-dimethyoxy-phenyl)-2-methyl-pyridin-2-yl]-propyl amine 202 propyl ethyl H 2,4-dimethoxyphenyl[5-ethyl-6-(2,4-dimethoxy- MS 343(M + H) NMR 7.22(s, 1H),phenyl)-2-methyl-pyridin-3- 7.18(d, 1H), 6.55(d, 1H), 6.50(s, 1H)yl]-ethyl-propyl-amine 3.86(s, 3H), 3.74(s, 3H), 3.02(s, 4H), 2.94(t,2H), 2.53(s, 3H), 2.39(q, 4H), 1.49(m, 2H), 1.04(m, 6H), 0.90(t, 3H) 203propyl butyl Cl 2,4-dimethoxyphenyl [5-ethyl-4-chloro-6-(2,4- MS 390(M +H) NMR 7.12(d, 1H), dimethoxy-phenyl)-2-methyl- 6.56(d, 1H), 6.50(s,1H), 3.86(s, 3H) pyridin-3-yl]-propyl-butyl- 3.74(s, 3H), 3.07(t, 4H),2.58(s, 3H), amine 2.50(m, 2H), 1.49(m, 4H), 0.99(t, 3H), 0.90(t, 6H).204 3-methyl propyl methoxy 2,4-dimethoxyphenyl3-Methyl-butyl-[5-Ethyl-4- MS 415(M + H) NMR 7.15(d, 1H), butylmethoxy-6-2,4-dimethyoxy- 6.54(d, 1H), 6.51(s, 1H), 3.89(s, 3H)phenyl)-2-methyl-pyridin-3- 3.86(s, 3H), 3.72(s, 3H), 3.04(m, 4H),yl]-propyl-amine 2.52(s, 3H), 2.49(m, 2H), 1.52(m, 3H), 1.40(m, 2H),0.90(m, 12H).

TABLE IV

Cmp Analytical Data # R_(X) R_(Y) R₁ R₄ R₅ R₆ IUPAC Name MS(M + 1) 205 H1-ethyl-propyl CH₃O CH₃ CH₃O CF₃O N-(1-ethylpropyl)-2-methoxy-6-[2-399.3 methoxy-4-(trifluoromethoxy)phenyl]-5- methylpyridin-3-amine 206 H1-ethyl-propyl CH₃CH₂O CH₃ CH₃O CF₃O 2-ethoxy-N-(1-ethylpropyl)-6-[2-413.4 methoxy-4-(trifluoromethoxy)phenyl]-5- methylpyridin-3-amine 207propyl propyl CH₃CH₂ CH₃ CH₃O CF₃O 2-ethyl-6-[2-methoxy-4- 411(trifluoromethoxy)phenyl]-5-methyl-N,N- dipropylpyridin-3-amine 208 Hpropyl CH₃CH₂ CH₃ CH₃O CF₃O 2-ethyl-6-[2-methoxy-4- 369.2(trifluoromethoxy)phenyl]-5-methyl-N- propylpyridin-3-amine 209 H1-ethyl-propyl CH₃CH₂ CH₃ CH₃O CF₃O 2-ethyl-N-(1-ethylpropyl)-6-[2- Rf0.45 methoxy-4-(trifluoromethoxy)phenyl]-5- (5% MeOH inmethylpyridin-3-amine dichloromethane) 210 H CH₃(CH₂)₂(C═O) CH₃O CH₃CH₃O CF₃O N-[2-methoxy-6-[2- 399.3methoxy-4-(trifluoromethoxy)phenyl]-5- methylpyridin-3-yl]butanamineAdditional compounds of Formula I.

-   211.    N,N-diethyl-6-[2-methoxy-4-(trifluoromethoxy)phenyl]-5-methyl-2-(methylamino)nicotinamide    MS (M+1): 426.4-   212.    2-Ethyl-1-[5-ethyl-6-(4-isopropoxy-2-methoxy-phenyl)-2-methoxy-pyridin-3-yl]-butan-1-ol-   213.    5-Ethyl-6-(4-isopropoxy-2-methoxy-phenyl)-2-methylamino-N,N-dipropyl-nicotinamide

Example 10 Additional Compounds of Formula I

The R₂-Matrix, Het-Matrix, and Ar-Matrix tables below set forth a numberof additional compounds of Formula I. Compounds are formed by combiningany element from the R₂ Matrix with any element from the Het-matrix toform an R₂—Het moiety, and then combining this moiety with any elementof the Ar-Matrix to form a compound of Formula I. For example, thecombination of element 143 from the R₂-Matrix, with element 203 from theHet-matrix, gives the moiety 143203. This moiety is then combined withelement 304 from the Ar-matrix, to form a compound of Formula I,compound 143203304, which is[6-(2,4-Dimethoxy-phenyl)-2,5-diethyl-pyridin-3-yl]-(1-ethyl-propylamine.

Thus, the invention includes compounds of the formula R₂-Het-Ar and thepharmaceutically acceptable salts thereof, wherein R₂ is any element,102-151, of the R₂ Matrix, Het is any element, 201-232 of theHet-Matrix, and Ar is any element, 301-380 of the Ar-Matrix.

Example 11 Assay for CRF Receptor Binding Activity

As discussed above, the following assay is defined herein as a standardin vitro CRF receptor binding assay. The pharmaceutical utility ofcompounds of this invention is indicated by the following assay for CRF1receptor activity.

The CRF receptor binding is performed using a modified version of theassay described by Grigoriadis and De Souza (Methods in Neurosciences,Vol. 5, 1991). IMR-32 human neuroblastoma cells, a cell line that can beinduced to express the CRF1 receptor, are cultured in growth mediumconsisting of EMEM w/Earle's BSS (JRH Biosciences, Cat# 51411)supplemented with 10% Fetal Bovine Serum, 25 mM HEPES (pH 7.2), 1 mMSodium Pyruvate, and Non-Essential Amino Acids (JRH Biosciences, Cat#58572). Stock cultures of cells are grown to confluence and subculturedtwice per week at split ratios of 1:2 to 1:4 (cells are dislodged duringsubculturing using No-Zyme, JRH Biosciences, Cat# 59226). To induce CRF1receptor expression, the cells are grown to approximately 80% confluenceand then changed to growth media containing 2.5 μM5-bromo-2′deoxyuridine (BrdU, Sigma, Cat# B9285). Growth mediacontaining BrdU is replaced every 3-4 days and the cells are harvestedvia centrifugation (using No-Zyme) after 10 days of BrdU treatment.Harvested cells are stored frozen at −80° C. until needed for thepreparation of membrane homogenates.

To prepare receptor-containing membranes cells are homogenized in washbuffer (50 mM Tris HCl, 10 mM MgCl₂, 2 mM EGTA, pH 7.4) and centrifugedat 48,000×g for 10 minutes at 4° C. The pellet is re-suspended in washbuffer and the homogenization and centrifugation steps are performedonce more.

Membrane pellets (containing CRF receptors) are resuspended and broughtto a final concentration of 1.0 mg membrane protein/ml in binding buffer(Tris buffer above with 0.1% BSA and 0.1 mM bacitracin). For the bindingassay, 150 microliters of the membrane preparation is added to 96 wellmicrotube plates containing 50 microliters of ¹²⁵I—CRF (SA 2200 Ci/mmol,final concentration of 100 pM) and 2 microliters of test compound.Binding is carried out at room temperature for 2 hours. Plates are thenharvested using 50 mM Tris buffer pH 7.4, on a BRANDEL 96 well cellharvester and filters (soaked in 1% PEI for 1.5 hours) are counted forgamma emissions on a Wallac 1205 BETAPLATE liquid scintillation counter.Non-specific binding is defined by 2 micromolar cold CRF. IC₅₀ valuesare calculated with the non-linear curve fitting program RS/1 (BBNSoftware Products Corp., Cambridge, Mass.).

The binding affinity for the compounds of Formula I expressed as an IC₅₀value, generally ranges from about 0.5 nanomolar to about 10 micromolar.Preferred compounds of Formula I exhibit IC₅₀ values of less than orequal to 1.5 micromolar, more preferred compounds of Formula I exhibitIC₅₀ values of less than 500 nanomolar, still more preferred compoundsof Formula I exhibit IC₅₀ values of less than 100 nanomolar, and mostpreferred compound of Formula I exhibit IC₅₀ values of less than 10nanomolar.

Compounds of Formula I shown in Examples 1-9 for which analytical datais provided have been tested in this assay and found to exhibit IC₅₀values of less than or equal to 4 micromolar.

Example 12 Preparation of Radiolabeled Probe Compounds of Formula I

The compounds of Formula I are prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon (preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). Suchradiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRIInternational, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using the compound ofFormula I as substrate. In addition, certain precursors may be subjectedto tritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

Example 13 Receptor Autoradiography

Receptor autoradiography (receptor mapping) is carried out in vitro asdescribed by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols inPharmacology (1998) John Wiley & Sons, New York, using radiolabeledcompounds of Formula I prepared as described in the preceding Examples.

Example 14 Additional Aspects of Preferred Compounds of Formula I

The most preferred compounds of Formula I are suitable forpharmaceutical use in treating human patients. Accordingly, suchpreferred compounds are non-toxic. They do not exhibit single ormultiple dose acute or long-term toxicity, mutagenicity (e.g., asdetermined in a bacterial reverse mutation assay such as an Ames test),teratogenicity, tumorogenicity, or the like, and rarely trigger adverseeffects (side effects) when administered at therapeutically effectivedosages.

Preferably, administration of such preferred compounds of Formula I atcertain doses (e.g., doses yielding therapeutically effective in vivoconcentrations or preferably doses of 10, 50, 100, 150, or 200mg/kg—preferably 150 mg/kg—administered parenterally or preferablyorally) does not result in prolongation of heart QT intervals (i.e., asdetermined by electrocardiography, e.g., in guinea pigs, minipigs ordogs). When administered daily for 5 or preferably ten days, such dosesof such preferred compounds also do not cause liver enlargementresulting in an increase of liver to body weight ratio of more than100%, preferably not more than 75% and more preferably not more than 50%over matched controls in laboratory rodents (e.g., mice or rats). Inanother aspect such doses of such preferred compounds also preferably donot cause liver enlargement resulting in an increase of liver to bodyweight ratio of more than 50%, preferably not more than 25%, and morepreferably not more than 10% over matched untreated controls in dogs orother non-rodent animals.

In yet another aspect such doses of such preferred compounds alsopreferably do not promote the release of liver enzymes (e.g., ALT, LDHor AST) from hepatocytes in vivo. Preferably such doses do not elevatesuch enzymes by more than 100%, preferably not by more than 75% and morepreferably not by more than 50% over matched untreated controls inlaboratory rodents. Similarly, concentrations (in culture media or othersuch solutions that are contacted and incubated with cells in vitro)equivalent to two, fold, preferably five-fold, and most preferablyten-fold the minimum in vivo therapeutic concentration do not causerelease of any of such liver enzymes from hepatocytes in vitro.

Because side effects are often due to undesirable receptor activation orantagonism, preferred compounds of Formula I exert theirreceptor-modulatory effects and bind to the CRF1 receptor with highselectivity. This means that they do not bind to certain other receptors(i.e., other than CRF receptors) with high affinity, but rather onlybind to, activate, or inhibit the activity of such other receptors withaffinity constants of greater than 100 nanomolar, preferably greaterthan 1 micromolar, more preferably greater than 10 micromolar and mostpreferably greater than 100 micromolar. Such receptors preferably areselected from the group including ion channel receptors, includingsodium ion channel receptors, neurotransmitter receptors such as alpha-and beta-adrenergic receptors, muscarinic receptors (particularly m1,m2, and m3 receptors), dopamine receptors, and metabotropic glutamatereceptors; and also include histamine receptors and cytokine receptors,e.g., interleukin receptors, particularly IL-8 receptors. The group ofother receptors to which preferred compounds do not bind with highaffinity also includes GABA_(A) receptors, bioactive peptide receptors(including NPY and VIP receptors), neurokinin receptors, bradykininreceptors (e.g., BK1 receptors and BK2 receptors), and hormone receptors(including thyrotropin releasing hormone receptors andmelanocyte-concentrating hormone receptors).

Example 15 Absence of Sodium Ion Channel Activity

Preferred compounds of Formula I do not exhibit activity as sodium ionchannel blockers. Sodium channel activity may be measured a standard invitro sodium channel binding assays such as the assay given by Brown etal. (J. Neurosci. (1986) 265: 17995-18004). Preferred compounds ofFormula I exhibit less than 15 percent inhibition, and more preferablyless than 10 percent inhibition, of sodium channel specific ligandbinding when present at a concentration of 4 uM. The sodium ion channelspecific ligand used may be labeled batrachotoxinin, tetrodotoxin, orsaxitoxin. Such assays, including the assay of Brown referred to above,are performed as a commercial service by CEREP, INC., Redmond, Wash.

Alternatively, sodium ion channel activity may be measured in vivo in anassay of anti-epileptic activity. Anti-epileptic activity of compoundsmay be measured by the ability of the compounds to inhibit hind limbextension in the supramaximal electroshock model. Male Han Wistar rats(150-200 mg) are dosed i.p. with a suspension of 1 to 20 mg of testcompound in 0.25% methylcellulose 2 hr. prior to test. A visualobservation is carried out just prior to testing for the presence ofataxia. Using auricular electrodes a current of 200 mA, duration 200milliseconds, is applied and the presence or absence of hind limbextension is noted. Preferred compounds of Formula I do not exhibitsignificant anti-epileptic activity at the p< 0.1 level of significanceor more preferably at the p< 0.05 level of significance as measuredusing a standard parametric assay of statistical significance such as astudent's T test.

Example 16 Optimal In Vitro Half-Life

Compound half-life values (t_(1/2) values) may be determined via thefollowing standard liver microsomal half-life assay. Liver microsomesare obtained from pooled liver samples and prepared so that the P-450enzyme content is approximately 0.5 nmol/mg protein. Reactions arepreformed in a 5 ml well deep-well plate as follows:

Phosphate buffer: 19 mL 0.1 M NaH₂PO₄, 81 mL 0.1 Na₂HPO₄, pH 7.4 withH₃PO₄.

CoFactor Mixture: 16.2 mg NADP, 45.4 mg Glucose-6-phosphate in 4 mL 100mM MgCl₂. Glucose-6-phosphate dehydrogenase: 214.3 microlitersglucose-6-phosphate dehydrogenase, 1285.7 microliters distilled water

Starting Reaction Mixture: 3 mL CoFactor Mixture, 1.2 mLGlucose-6-phosphate dehydrogenase

6 identical sample wells each containing 25 microliters microsomes, 5microliters test compound (from a 100 uM stock), and 399 microliters 0.1M phosphate buffer, pH 7.4, are prepared. A seventh well containing 25microliters microsomes, 399 microliters 0.1 M phosphate buffer, pH 7.4,and 5 microliters(from a 100 uM stock) of a compound, e.g. diazapam,clozapine, with known metabolic properties is used as a positivecontrol. Reactions are preincubated at 39° C. for 10 minutes. 71microliters Starting Reaction Mixture is added to 5 of the 6 reactionwells and to the positive control well, 71 microliters 100 mM MgCl₂ isadded to the sixth reaction well, which is used as a negative control.At each time point (0, 1, 3, 5, and 10 minutes) 75 microliters reactionis pipetted into a 96-well deep-well plate reaction well containing 75microliters ice-cold acetonitrile. Samples are vortexed and centrifuged10 minutes at 6000 rpm (Sorval T 6000D rotor). Supernatant, 75microliters from each reaction well, is transferred to a 96-well platecontaining 150 microliters internal standard per well. The remainingtest compound is quantitated via LCMS. Compound concentration vs lime isplotted and commercially available statistical software is used toextrapolate to the t_(1/2) value of the test compound.

Preferred compounds of Formula I exhibit in vitro t_(1/2) values ofgreater than 10 minutes and less than 4 hours. Most preferred compoundsof Formula I exhibit in vitro t_(1/2) values of between 30 minutes and 1hour in human liver microsomes.

Example 17 MDCK Toxicity

Compounds causing acute cytotoxicity will decrease ATP production byMadin Darby canine kidney (MDCK) cells in the following assay.

MDCK cells, ATCC no. CCL-34 (American Type Culture Collection, Manassas,Va.) are maintained in sterile conditions following the instructions inthe ATCC production information sheet. The PACKARD, (Meriden, Conn.)ATP-LITE-M Luminescent ATP detection kit, product no. 6016941, allowsmeasurement ATP production in MDCK cells.

Prior to assay 1 microliter of test compound or control sample ispipetted into PACKARD (Meriden, Conn.) clear bottom 96-well plates. Testcompounds and control samples are diluted in DMSO to give finalconcentration in the assay of 10 micromolar, 100 micromolar, or 200micromolar. Control samples are drug or other compounds having knowntoxicity properties.

Confluent MDCK cells are trypsinized, harvested, and diluted to aconcentration of 0.1×10⁶ cells/ml with warm (37° C.) VITA CELL MinimumEssential Medium Eagle (ATCC catalog #30-2003). 100 microliters of cellsin medium is pipetted into each of all but five wells of each 96-wellplate. Warm medium without cells (100ul) is pipetted in the remainingfive wells of each plate. These wells, to which no cells are added, areused to determine the standard curve. The plates are then incubated at37° C. under 95% O₂, 5% CO₂ for 2 hours with constant shaking. Afterincubation, 50 microliters of mammalian cell lysis solution is added perwell, the wells are covered with PACKARD TOPSEAL stickers, and platesare shaken at approximately 700 rpm on a suitable shaker for 2 minutes.

During the incubation, PACKARD ATP LITE-M reagents are allowed toequilibrate to room temperature. Once equilibrated the lyophilizedsubstrate solution is reconstituted in 5.5 ml of substrate buffersolution (from kit). Lyophilized ATP standard solution is reconstitutedin deionized water to give a 10 mM stock. For the five control wells, 10microliters of serially diluted PACKARD standard is added to each of thefive standard curve control wells to yield a final concentration in eachsubsequent well of 200 nM, 300 nM, 50 nM, 25 nM, and 12.5 nM.

PACKARD substrate solution (50 ul) is added to all wells. Wells arecovered with PACKARD TOPSEAL stickers, and plates are shaken atapproximately 700 rpm on a suitable shaker for 2 minutes. A whitePACKARD sticker is attached to the bottom of each plate and samples aredark adapted by wrapping plates in foil and placing in the dark for 10minutes. Luminescence is then measured at 22° C. using a luminescencecounter, e.g. PACKARD TOPCOUNT Microplale Scintillation and LuminescenceCounter or TECAN SPECTRAFLUOR PLUS.

Luminescence values at each drug concentration are compared to thevalues computed from the standard curve for that concentration.Preferred test compounds exhibit luminescence values 80% or more of thestandard, or preferably 90% or more of the standard, when a 10micromolar (uM) concentration of the test compound is used. When a 100micromolar concentration of the test compound is used, preferred testcompounds exhibit luminescence values 50% or more of the standard, ormore preferably 80% or more of the standard.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ar is mono-,di-, or tri-substituted heteroaryl, said heteroaryl having from 1 to 3rings, 5 to 7 ring members in each ring and from 1 to about 3heteroatoms in at least one of said rings; R is oxygen or absent; R₂ isoptionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted alkoxy, optionallysubstituted mono or dialkylamino, optionally substituted alkylthio,optionally substituted alkylsulfinyl, optionally substitutedalkylsulfonyl, optionally substituted mono or dialkylcarboxamide,optionally substituted aryl or optionally substituted heteroaryl, saidheteroaryl having from 1 to 3 rings, 5 to 7 ring members in each ringand from 1 to about 3 heteroatoms in at least one of said rings; R₁, R₃,and R₄ are independently chosen from hydrogen, halogen, nitro,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted alkoxy, optionallysubstituted mono- or di-alkylamino, optionally substituted cycloalkyl,optionally substituted (cycloalkyl)alkyl, optionally substituted(cycloalkyl)oxy, optionally substituted (cycloalkyl)alkoxy, optionallysubstituted alkylthio, optionally substituted alkylsulfinyl, optionallysubstituted alkylsulfonyl, and optionally substituted mono- ordialkylcarboxamide, with the proviso that not all of R₁, R₂, R₃, and R₄are unsubstituted alkyl and not all of R₅, R₃, and R₄ are hydrogen. 2.(canceled)
 3. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein: Ar is selectedfrom the group consisting of pyridyl, pyrimidinyl, pyrazinyl,pyridizinyl, and thiophenyl, each of which is substituted with up to 5R_(A) groups; R is oxygen or absent; R₁, R₃, and R₄ are independentlyselected from hydrogen, halogen, hydroxy, amino, nitro,C₁-C₆carbhydryl₁, C₁-C₆carbhydryl₁-O—, mono- ordi-C₁-C₆carbhydryl₁amino, C₃-C₇cycloalkyl₂(C₀-C₄-carbhydryl₁),C₃-C₇cycloalkenyl₂(C₀-C₄-carbhydryl₁),C₃-C₇cycloalkyl₂(C₀-C₄-carbhydryl₁)—O—,C₃-C₇cycloalkenyl₂(C₀-C₄-carbhydryl₁)—O—, haloC₁-C₆carbhydryl₁,haloC₁-C₆carbhydryl₁-O—, and —S(O)_(n)(C₁-C₆carbhydryl₁), where eachcarbhydryl₁ is independently straight or branched, contains 0or 1 ormore double or triple bonds, and is unsubstituted or substituted withone or more substituents independently chosen from halogen, hydroxy,oxo, cyano, C₁-C₄alkoxy, amino, and mono- or di-(C₁-C₄alkyl)amino, andwhere each C₃-C₇cycloalkyl₂ and C₃-C₇cycloalkenyl₂ is optionallysubstituted by one or more substituents independently chosen fromhalogen, hydroxy, oxo, cyano, C₁-C₄alkoxy, amino, and mono- or di-(CVC₄)alkylamino, R₂ is selected from the group consisting of —XR_(C) andY; X is independently selected at each occurrence from the groupconsisting of —CH₂—, —CHR_(D)—, —O—, —C(═O)—, —C(═O)_(n)—, —S(O)_(n)—,—NH—, —NR_(D)—, —C(═O)NH—, —C(═O)NR_(D)—, —S(O)_(n)NH—,—S(O)_(n)NR_(D)—, —OC(═S)S—, —NHC(═O)—, —NR_(D)C(═O)—, —NHS(O)_(n)—, and—NR_(D)S(O)_(n)—; Y and Z are independently selected at each occurrencefrom: 3- to 7-membered carbocyclic or heterocyclic groups, which aresaturated, partially unsaturated, or aromatic, which may be furthersubstituted with one or more substituents independently selected fromhalogen, oxo, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, mono- ordi-(C₁-C₄alkyl)amino, and —S(O)_(n)(alkyl), wherein said 3- to7-membered heterocyclic groups contain from 1 to 3 heteroatom(s)independently selected from N, O, and S, with remaining ring membersbeing carbon; R_(A) is independently selected at each occurrence fromhalogen, cyano, nitro, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, hydroxy,amino, C₁-C₆alkyl substituted with 0-2 R_(B), C₂-C₆alkenyl substitutedwith 0-2 R_(B), C₂-C₆alkynyl substituted with 0-2 R_(B), C₃-C₇cycloalkylsubstituted with 0-2 R_(B), (C₃-C₇cycloalkyl)C₁-C₄alkyl substituted with0-2 R_(B), C₁-C₆alkoxy substituted with 0-2 R_(B), —NH(C₁-C₆alkyl)substituted with 0-2 R_(B), N(C₁-C₆alkyl)(C₁-C₆alkyl) where eachC₁-C₆alkyl is independently substituted with 0-2 R_(B), —XR_(C), and Y;R_(B) is independently selected at each occurrence from halogen,hydroxy, cyano, amino, C₁-C₄alkyl, C₁-C₄alkoxy, mono- ordi-(C₁-C₄alkyl)amino, —S(O)_(n)(alkyl), halo(C₁-C₄)alkyl,halo(C₁-C₄)alkoxy, —CO(C₁-C₄alkyl), —CONH(C₁-C₄alkyl),—CON(C₁-C₄alkyl)(C₁-C₄alkyl), —XR_(C), and Y; R_(C) and R_(D), are thesame or different, and are independently selected at each occurrencefrom: hydrogen, and straight, branched, and cyclic alkyl groups, and(cycloalkyl)alkyl groups, having 1 to 8 carbon atoms, and containingzero or one or more double or triple bonds, each of which 1 to 8 carbonatoms may be further substituted with one or more substituent(s)independently selected from oxo, hydroxy, halogen, cyano, amino,C₁-C₆alkoxy, mono- or di-(C₁-C₄alkyl)amino, —NHC(═O)(C₁-C₆alkyl),—N(C₁-C₆alkyl)C(═O)(C₁-C₆alkyl), —NHS(O)_(n)(C₁-C₆alkyl),—S(O)_(n)(C₁-C₆alkyl), —S(O)_(n)NH(C₁-C₆alkyl),—S(O)_(n)N(C₁-C₆alkyl)(C₁-C₆alkyl), and Z; and n is independentlyselected at each occurrence from 0, 1, and 2; with the proviso that notall of R₁, R₂, R₃, and R₄ are unsubstituted alkyl and not all of R₁, R₃,and R₄ are hydrogen.
 4. (canceled)
 5. A compound or salt according toclaim 3, wherein R is absent and Ar is pyridyl, which is substitutedwith R_(A) in at least 1 position ortho to the point of attachment of Arin Formula I, and optionally substituted with up to 2 additional R_(A)groups.
 6. A compound or salt according to claim 5 wherein R is absent;R₁, R₃, and R₄ are independently selected from the group consisting ofi) hydrogen, ii)halogen, iii) C₁-C₃alkyl, iv) C₁-C₃alkoxy, v)(C₃-C₇cycloalkyl)C₀-C₃alkyl, vi) (C₃-C₇cycloalkyl)C₀-C₃alkoxy, vii)mono- or di-(C₁-C₃alkyl)amino, viii)C₁-C₃haloalkyl, and ix)C₁-C₃haloalkoxy wherein each of iii, iv, v, vi, and vii is unsubstitutedor substituted by 1-3 groups independently chosen from hydroxy, amino,cyano, and halogen.
 7. A compound or salt according to claim 3, wherein:R is absent; Ar is pyridyl, which is substituted with R_(A) in at least1 position ortho to the point of attachment of Ar in Formula I, andoptionally substituted with up to 2 additional R_(A) groups; and R_(C)and R_(D), which may be the same or different, are independentlyselected at each occurrence from straight, branched, or cyclic alkylgroups having from 1 to 8 carbon atoms, which alkyl groups may containone or more double or triple bonds.
 8. A compound or salt according toclaim 7, wherein: R₁, R₃ and R₄ are independently selected from thegroup consisting of i) hydrogen, ii) halogen, iii) C₁-C₃alkyl, iv)C₁-C₃alkoxy, v) (C₃-C₇cycloalkyl)C₀-C₃alkyl, vi)(C₃-C₇cycloalkyl)C₀-C₃alkoxy, vii) mono- or di-(C₁-C₃alkyl)amino,viii)C₁-C₃haloalkyl, and ix) C₁-C₃haloalkoxy, wherein each of iii, iv,v, vi, and vii is unsubstituted or substituted by 1-3 groupsindependently chosen from hydroxy, amino, cyano, and halogen.
 9. Acompound or salt according to claim 3, wherein: R is absent; Ar pyridylwhich is substituted in at least one position ortho to the point ofattachment of Ar in Formula I with a substituent selected from halogen,cyano, nitro, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, hydroxy, amino,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl,(C₃-C₇cycloalkyl)C₁-C₄alkyl, C₁-C₆alkoxy, and mono- ordi-(C₁-C₆alkyl)amino and optionally substituted with up to 2 additionalsubstituents independently selected from halogen, cyano, nitro,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, hydroxy, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl,(C₃-C₇cycloalkyl)C₁-C₄alkyl, C₁-C₆alkoxy, and mono- ordi-(C₁-C₆alkyl)amino; R₁, R₃ and R₄ are independently selected from thegroup consisting of i) hydrogen, ii)halogen, iii) C₁-C₃alkyl, iv)C₁-C₃alkoxy, v) (C₃-C₇cycloalkyl)C₀-C₃alkyl, vi)(C₃-C₇cycloalkyl)C₀-C₃alkoxy, vii) mono- or di-(C₁-C₃alkyl)amino,viii)C₁-C₃haloalkyl, and ix) C₁-C₃haloalkoxy, wherein each of iii, iv,v, vi, and vii is unsubstituted or substituted by 1-3 groupsindependently chosen from hydroxy, amino, cyano, and halogen.
 10. Acompound or salt according to claim 9, wherein R₂ is —XR_(C); X isindependently selected at each occurrence from the group consisting of—CH₂—, —CHR_(D)—, —O—, —C(═O)—, —NH—, —NR_(D)—, —C(═O)NH—,—C(═O)NR_(D)—, —NHC(═O)—, —NR_(D)C(═O)—, R_(C) and R_(D), are the sameor different, and are independently selected at each occurrence from:hydrogen, and straight, branched, and cyclic alkyl groups, and(cycloalkyl)alkyl groups, having 1 to 8 carbon atoms, and containingzero or one or more double or triple bonds, each of which 1 to 8 carbonatoms may be further substituted with one or more substituent(s)independently selected from oxo, hydroxy, halogen, cyano, amino,C₁-C₆alkoxy, and mono- and di(C₁-C₆alkyl)amino.
 11. A compound or saltaccording to claim 10, wherein X is independently selected at eachoccurrence from the group consisting of —CH₂—, —CHR_(D)—, —O—, —NH—, -and NR_(D)—; R_(C) and R_(D), are the same or different, and areindependently selected at each occurrence from: hydrogen, and straight,branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, having1 to 8 carbon atoms, and containing zero or one or more double or triplebonds.
 12. A compound or salt according to claim 3 of Formula II

wherein: R_(X) and R_(Y) are the same or different and are independentlyselected from: a) hydrogen, b) —(C═O)C₁-C₈alkyl; and c) straight orbranched alkyl groups, cycloalkyl groups, or (cycloalkyl)alkyl groups,having 1 to 8 carbon atoms and containing zero or more double or triplebonds, each of which 1 to 8 carbon atoms may be further substituted withone or more substituent(s) independently selected from: i) halogen,hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono- or di-(CVC₄alkyl)amino, and ii) 3- to 7-membered carbocyclic or heterocyclicgroups which are saturated, partially unsaturated, or aromatic, whichmay be further substituted with one or more substituents independentlyselected from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,and mono- or di-(C₁-C₄alkyl)amino, wherein said 3- to 7-memberedheterocyclic groups contain from 1 to 3 heteroatom(s) independentlyselected from N, O, and S, with remaining ring members being carbon. 13.A compound or salt according to claim 12, wherein: R_(X) and R_(Y) arethe same or different and are independently selected from: a) hydrogen,b) —(C═O)C₁-C₈alkyl, and c) straight or branched alkyl groups,cycloalkyl groups, or (cycloalkyl)alkyl groups, having 1 to 8 carbonatoms and containing zero or more double or triple bonds, each of which1 to 8 carbon atoms may be further substituted with one or moresubstituent(s) independently selected from: halogen, hydroxy, amino,cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono- or di-(CV C₄alkyl)amino, Ar ispyridyl which is mono-, di-, or tri-substituted with R_(A), with theproviso that at least one of the positions ortho to the point ofattachment of Ar shown in Formula II is substituted; X is independentlyselected at each occurrence from the group consisting of —CH₂—,—CHR_(D)—, —O—, —C(═O)—, —C(═O)O—, —NH—, —NR_(D)—, —C(═O)NH—,—C(═O)NR_(D)—, —NHC(═O)—, and —NR_(D)C(═O)—; Y and Z are independentlyselected at each occurrence from: 3- to 7-membered carbocyclic orheterocyclic groups which are saturated, partially unsaturated, oraromatic, which may be further substituted with one or more substituentsindependently selected from halogen, oxo, hydroxy, amino, cyano,C₁-C₄alkyl, C₁-C₄alkoxy, mono- or di-(C₁-C₄alkyl)amino, wherein said 3-to 7-membered heterocyclic groups contain from 1 to 3 heteroatom(s)independently selected from N, O, and S, with remaining ring membersbeing carbon; and R_(C) and R_(D), are the same or different, and areindependently selected at each occurrence from: hydrogen, and straight,branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, having1 to 8 carbon atoms, and containing zero or one or more double or triplebonds, each of which 1 to 8 carbon atoms may be further substituted withone or more substituent(s) independently selected from oxo, hydroxy,halogen, cyano, amino, C₁-C₆alkoxy, mono- or di-(C₁-C₄alkyl)amino,—NHC(═O)(C₁-C₆alkyl), —N(C₁-C₆alkyl)C(═O)(C₁-C₆alkyl), and Z.
 14. Acompound or salt according to claim 12, wherein: R₁, R₃ and R₄ areindependently selected from the group consisting of i) hydrogen,ii)halogen, iii) C₁-C₄alkyl, iv) C₁-C₃alkoxy, v)(C₃-C₇cycloalkyl)C₀-C₃alkyl, yl) (C₃-C₇Cycloalkyl)C₀-C₃alkoxy, vii)mono- or di-(C₁-C₃alkyl)amino, viii)CV C₃haloalkyl, and ix)C₁-C₃haloalkoxy, wherein each of iii, iv, v, vi, and vii isunsubstituted or substituted by 1-3 groups independently chosen fromhalogen, hydroxy, oxo, cyano, C₁-C₄alkoxy, amino, and mono- ordi-(C₁-C₄alkyl)amino.
 15. A compound or salt according to claim 13,wherein R_(X) is a) hydrogen or b) a straight or branched alkyl group, acycloalkyl groups, or (cycloalkyl)alkyl group, each of which groupshaving 1 to 8 carbon atoms and containing zero or more double or triplebonds, each of which 1 to 8 carbon atoms may be further substituted withone or more substituent(s) independently selected from halogen, hydroxy,amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono- ordi-(C₁-C₄)alkylamino; R_(Y) is a straight or branched alkyl group, acycloalkyl groups, or (cycloalkyl)alkyl group, each of which groupshaving 1 to 8 carbon atoms and containing zero or more double or triplebonds, each of which 1 to 8 carbon atoms may be further substituted withone or more substituent(s) independently selected from halogen, hydroxy,amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono- ordi-(C₁-C₄)alkylamino; Ar is pyridyl, mono-, di-, or tri-substituted withsubstituents independently selected at each occurrence from halogen,cyano, nitro, halo(C₁-C₆)alkyl, halo(d-C₆)alkoxy, hydroxy, amino,C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,(C₃-C₇cycloalkyl)C₁-C₄alkyl, C₁-C₆alkoxy, and mono- ordi-(C₁-C₆alkyl)amino; and R₁, R₃ and R₄ are independently selected fromthe group consisting of hydrogen, halogen, C₁-C₄alkyl, C₁-C₃alkoxy,(C₃-C₇cycloalkyl)C₀-C₃alkyl, (C₃-C₇cycloalkyl)C₀-C₃alkoxy, mono- ordi-(C₁-C₃alkyl)amino, C₁-C₃haloalkyl, and C₁-C₃haloalkoxy.
 16. Acompound or salt according to claim 15, wherein R_(X) is hydrogen,C₁-C₆alkyl, a C₃-C₇cycloalkyl, or (C₃-C₇cycloalkyl) C₁-C₄alkyl; R_(Y) aC₁-C₆alkyl, a C₃-C₇cycloalkyl, or (C₃-C₇cycloalkyl) C₁-C₄alkyl; Ar isphenyl mono-, di-, or tri-substituted with substituents independentlyselected at each occurrence from halogen, halo(C₁-C₂)alkyl,halo(C₁-C₂)alkoxy, hydroxy, amino, C₁-C₃ alkyl, C₁-C₂alkoxy, and mono-or di-(C₁-C₂alkyl)amino; and R₁ and R₄ are independently selected fromthe group consisting of hydrogen, halogen, C₁-C₃alkyl, C₁-C₃alkoxy,mono- or di-(C₁-C₃alkyl)amino, C₁-C₃haloalkyl, and C₁-C₃haloalkoxy; andR₃ is hydrogen, halogen, or methyl.
 17. A compound or salt according toclaim 12 of Formula III:

wherein: A is N; and R₅, R₆, and R₇ are independently i) hydrogen,halogen, cyano, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino,C₁-C₆alkyl, C₁-C₆alkoxy, (C₁-C₄alkoxy) C₁-C₄alkoxy, or mono- ordi(C₁-C₄alkyl)amino, or ii) C₁-C₆alkyl or C₁-C₆alkoxy, each of which isfurther substituted with a 3- to 7-membered carbocyclic or heterocyclicgroups which is saturated, partially unsaturated, or aromatic, which maybe further substituted with one or more substituents independentlyselected from halogen, oxo, hydroxy, amino, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, and mono- or di-(C₁-C₄alkyl)amino; wherein at least one ofR₅ and R₇ is not hydrogen.
 18. A compound or salt according to claim 17,wherein: R_(X) is a) hydrogen or b) a straight or branched alkyl group,a cycloalkyl group, or (cycloalkyl)alkyl group, having 1 to 8 carbonatoms and containing zero or more double or triple bonds, each of which1 to 8 carbon atoms may be further substituted with one or moresubstituent(s) independently selected from halogen, hydroxy, amino,cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono- or di-(C₁-C₄)alkylamino; R_(Y)is a straight or branched alkyl group, a cycloalkyl group, or(cycloalkyl)alkyl group, each having 1 to 8 carbon atoms and containingzero or more double or triple bonds, each of which 1 to 8 carbon atomsmay be further substituted with one or more substituent(s) independentlyselected from halogen, hydroxy, amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy,and mono- or di-(C₁-C₄)alkylamino; R₁ and R₄ are independently selectedfrom the group consisting of hydrogen, halogen, C₁-C₄alkoxy,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, and C₁-C₆alkyl, which C₁₋₆alkyl isunsubstituted or substituted by one to three substituents independentlyselected from hydroxy, oxo, cyano, C₁-C₄alkoxy, amino, and mono- ordi(C₁-C₄)alkylamino, R₃ is hydrogen, halogen, methyl, or methoxy; andR₅, R₆, and R₇ are independently selected from hydrogen, halogen, cyano,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino, C₁-C₆alkyl,C₁-C₆alkoxy, (C₁-C₄alkoxy)C₁-C₄alkoxy, and mono- or di(C₁-C₄alkyl)amino.19. A compound or salt according to claim 3 of Formula IV

wherein R_(X) and R_(Y) are joined to form a saturated 5 to 7 memberedheterocycloalkyl ring containing 0 or 1 additional heteroatom selectedfrom N, O, and S, wherein said saturated 5 to 7 memberedheterocycloalkyl ring is optionally substituted with from 1 to 4 groupsindependently chosen from halogen, hydroxy, methyl and methoxy.
 20. Acompound or salt according to claim 12 of Formula V:

wherein: Ar is pyridyl which is mono-, di-, or tri-substituted withR_(A), with the proviso that at least one of the positions ortho to thepoint of attachment of Ar shown in Formula V is substituted; R₁ and R₄are independently selected from the group consisting of hydrogen,halogen, C₁-C₄alkoxy, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, C₁-C₆alkyl,and mono- and di-(C₁-C₄alkyl)amino; and R₉ is selected from straight orbranched alkyl groups, cycloalkyl groups, and (cycloalkyl)alkyl groups,having 1 to 8 carbon atoms and containing zero or more double or triplebonds, each of which 1 to 8 carbon atoms may be further substituted withone or more substituent(s) independently selected from oxo, hydroxy,halogen, cyano, C₁-C₄alkoxy, amino, and mono- or di-(C₁-C₄)alkylamino.21. A compound or salt according to claim 20 of Formula VI:

wherein, A is N; and R₅, R₆, and R₇ are independently i) hydrogen,halogen, cyano, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino,Q-C₆alkyl, C₁-C₆alkoxy, (C₁-C₄alkoxy) C₁-C₄alkoxy, or mono- ordi(C₁-C₄alkyl)amino, or ii) C₁-C₆alkyl or C₁-C₆alkoxy, each of which isfurther substituted with a 3- to 7-membered carbocyclic or heterocyclicgroups which is saturated, partially unsaturated, or aromatic, which maybe further substituted with one or more substituents independentlyselected from halogen, oxo, hydroxy, amino, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, and mono- or di-(C₁-C₄alkyl)amino; wherein at least one ofR₅ and R₇ is not hydrogen.
 22. A compound or salt according to claim 20,of Formula VII:

wherein: A is N; q is an integer from 1 to 4; G is hydrogen, hydroxy,C₁-C₄alkoxy, mono- or di(C₁-C₄alkyl)amino, or a 3- to 7-memberedcarbocyclic or heterocyclic group which is saturated, partiallyunsaturated, or aromatic, which may be further substituted with one ormore substituents independently selected from halogen, oxo, hydroxy,amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, mono- or di-(C₁-C₄alkyl)amino and—S(O)_(n)(alkyl), wherein said 3- to 7-membered heterocyclic groupcontains from 1 to 3 heteroatom(s) independently selected from N, O, andS, with remaining ring members being carbon, and n is 0, 1, or 2; and Jand K are independently selected from hydrogen, halogen, cyano,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino, C₁-C₆alkyl,C₁-C₆alkoxy, (C₁-C₄alkoxy)C₁-C₄alkoxy, and mono- or di(C₁-C₄alkyl)amino.23. A compound or salt according to claim 3 of Formula VIII

wherein: R_(X) is a straight or branched alkyl group, cycloalkyl group,or (cycloalkyl)alkyl group, having 1 to 8 carbon atoms and containingzero or more double or triple bonds, each which 1 to 8 carbon atoms maybe further substituted with one or more substituent(s) independentlyselected from: i) halogen, hydroxy, amino, cyano, d-C₄alkyl,C₁-C₄alkoxy, and mono- or di-(C₁-C₄alkyl)amino, ii) 3- to 7-memberedcarbocyclic or heterocyclic groups which are saturated, partiallyunsaturated, or aromatic, which may be further substituted with one ormore substituents independently selected from halogen, hydroxy, amino,cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono- or di-(C₁-C₄alkyl)amino,wherein said 3- to 7-membered heterocyclic groups contain from 1 to 3heteroatom(s) independently selected from N, O, and S, with remainingring members being carbon.
 24. A compound or salt according to claim 23,wherein: Ar is pyridyl which is mono-, di-, or tri-substituted withR_(A), with the proviso that at least one of the positions ortho to thepoint of attachment of Ar shown in Formula VIII is substituted; X isindependently selected at each occurrence from the group consisting of—CH₂—, —CHR_(D)—, —O—, —C(═O)—, —C(═O)—, —NH—, —NR_(D)—, —C(═O)NH—,—C(═O)NR_(D)—, —NHC(═O)—, and —NR_(D)C(═O)—; Y and Z are independentlyselected at each occurrence from: 3- to 7-membered carbocyclic orheterocyclic groups which are saturated, partially unsaturated, oraromatic, which may be further substituted with one or more substituentsindependently selected from halogen, oxo, hydroxy, amino, cyano,C₁-C₄alkyl, —O(C₁-C₄alkyl), and —NH(C₁-C₄alkyl),—N(C₁-C₄alkyl)(C₁-C₄alkyl), wherein said 3- to 7-membered heterocyclicgroups contain from 1 to 3 heteroatom(s) independently selected from N,O, and S, with remaining ring members being carbon; and R_(C) and R_(D),are the same or different, and are independently selected at eachoccurrence from: hydrogen, and straight, branched, and cyclic alkylgroups, and (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms, andcontaining zero or one or more double or triple bonds, each of which 1to 8 carbon atoms may be further substituted with one or moresubstituent(s) independently selected from oxo, hydroxy, halogen, cyano,amino, C₁-C₆alkoxy, mono- or di-(C₁-C₄alkyl)amino, —NHC(═O)(C₁-C₆alkyl),—N(C₁-C₆alkyl)C(═O)(C₁-C₆alkyl), and Z.
 25. A compound or salt accordingto claim 23, wherein: R₁R₃ and R₄ are independently selected from thegroup consisting of i) hydrogen, ii)halogen, iii) C₁-C₄alkyl, iv)C₁-C₃alkoxy, v) (C₁-C₃cycloalkyl)C₀-C₃alkyl, vi)(C₃-C₇cycloalkyl)C₀-C₃alkoxy, vii) mono- or di-(C₁-C₃alkyl)amino,viii)C₁-C₃haloalkyl, and ix) C₁-C₃haloalkoxy, wherein each of iii, iv,v, vi, and vii is unsubstituted or substituted by 1-3 groupsindependently chosen from halogen, hydroxy, oxo, cyano, C₁-C₄alkoxy,amino, and mono- or di-(C₁-C₄alkyl)amino.
 26. A compound or saltaccording to claim 24, wherein R_(X) is a straight or branched alkylgroup, a cycloalkyl groups, or (cycloalkyl)alkyl group, having 1 to 8carbon atoms and containing zero or more double or triple bonds, each ofwhich 1 to 8 carbon atoms may be further substituted with one or moresubstituent(s) independently selected from halogen, hydroxy, amino,cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono- or di-(C₁-C₄)alkylamino; Ar ispyridyl, mono-, di-, or tri-substituted with substituents independentlyselected at each occurrence from halogen, cyano, nitro,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, hydroxy, amino, C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl,(C₃-C₇cycloalkyl)C₁-C₄alkyl, C₁-C₆alkoxy, and mono- ordi-(C₁-C₆alkyl)amino; and R₁, R₃ and R₄ are independently selected fromthe group consisting of hydrogen, halogen, C₁-C₄alkyl, C₁-C₃alkoxy,(C₃-C₇cycloalkyl)C₀-C₃alkyl, (C₃-C₇cycloalkyl)C₀-C₃alkoxy, mono- ordi-(C₁-C₃alkyl)amino, C₁-C₃haloalkyl, and C₁-C₃haloalkoxy.
 27. Acompound or salt according to claim 26, wherein R_(X) is a C₁-C₆alkyl,C₃-C₇cycloalkyl, or (C₃-C₇cycloalkyl) C₁-C₄alkyl group; Ar is phenyl orpyridyl, mono-, di-, or tri-substituted with substituents independentlyselected at each occurrence from halogen, halo(C₁-C₂)alkyl,halo(C₁-C₂)alkoxy, hydroxy, amino, C₁-C₃alkyl, C₁-C₂alkoxy, and mono- ordi-(C₁-C₂alkyl)amino; and R₁ and R₄ are independently selected from thegroup consisting of hydrogen, halogen, C₁-C₃alkyl, C₁-C₃alkoxy, mono- ordi-(C₁-C₃alkyl)amino, C₁-C₃haloalkyl, and C₁-C₃haloalkoxy; and R₃ ishydrogen, halogen, or methyl.
 28. A compound or salt according to claim23 of Formula IX:

wherein: A is N; and R₅, R₆, and R₇ are independently i) hydrogen,halogen, cyano, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino,C₁-C₆alkyl, C₁-C₆alkoxy, (C₁-C₄alkoxy) C₁-C₄alkoxy, or mono- ordi(C₁-C₄alkyl)amino, or ii) C₁-C₆alkyl or C₁-C₆alkoxy, each of which isfurther substituted with a 3- to 7-membered carbocyclic or heterocyclicgroups which is saturated, partially unsaturated, or aromatic, which maybe further substituted with one or more substituents independentlyselected from halogen, oxo, hydroxy, amino, cyano, C₁-C₄alkyl,C₁-C₄alkoxy, and mono- or di-(C₁-C₄alkyl)amino, wherein said 3- to7-membered heterocyclic group contains from 1 to 3 heteroatom(s)independently selected from N, O, and S, with remaining ring membersbeing carbon; wherein at least one of R₅ and R₇ is not hydrogen.
 29. Acompound or salt according to claim 28, wherein: R_(X) is a straight orbranched alkyl group, a cycloalkyl group, or (cycloalkyl)alkyl group,having 1 to 8 carbon atoms and containing zero or more double or triplebonds, each of which 1 to 8 carbon atoms may be further substituted withone or more substituent(s) independently selected from halogen, hydroxy,amino, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, and mono- ordi-(C₁-C₄)alkylamino; R₁ and R₄ are independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄alkoxy, halo(C₁-C₄)alkyl,halo(C₁-C₄)alkoxy, and C₁-C₆alkyl, which C₁₋₆alkyl is unsubstituted orsubstituted by one to three substituents independently selected fromhydroxy, oxo, cyano, C₁-C₄alkoxy, amino, and mono- ordi(C₁-C₄)alkylamino, R₃ is hydrogen, halogen, methyl, or methoxy; andR₅, R₆, and R₇ are independently selected from hydrogen, halogen, cyano,halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, hydroxy, amino, C₁-C₆alkyl,C₁-C₆alkoxy, (C₁-C₄alkoxy)C₁-C₄alkoxy, and mono- or di(C₁-C₄alkyl)amino.30-32. (canceled)
 33. A method for treating anxiety, depression,irritable bowel syndrome, Crohn's disease, or stress comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of a compound or salt according to claim
 3. 34.(canceled)
 35. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a compound or salt of claim 3.36. A pharmaceutical composition according to claim 35, wherein thecomposition is formulated as an injectable fluid, an aerosol, a cream, agel, a tablet, a pill, a capsule, a syrup or a transdermal patch.
 37. Apackage comprising a pharmaceutical composition of claim 35 in acontainer and further comprising at least one of: instructions for usingthe composition to treat a patient suffering from anxiety, orinstructions for using the composition to treat a patient suffering fromstress, or instructions for using the composition to treat a patientsuffering from depression or instructions for using the composition totreat a patient suffering from Crohn's disease, or instructions forusing the composition to treat a patient suffering from irritable bowelsyndrome. 38-44. (canceled)